A recent protocol that has begun trials in the University of Pittsburgh is the insertion of the interleukin-4 gene into fibroblasts of patients, and the subsequent injection into patients with advanced breast, colon or kidney cancer; GEN (15 Oct 1993), 21. The patients also receive some of their own tumour cells, in an attempt to immunize the patient against their cancer. A review of new cancer therapies is in GEN (1 Oct 1993), 22-3. The total number of approved trials of gene therapy by the NIHRAC as of late September was 58; Biotechnology 11 (1993), 1227. In the September meeting 2 for HIV and 5 for cancer were added to the long list. A general review of gene therapy progress is JAMA 270 (1993), 2338-45; Scientific American (Dec 1993), 10-1.

The partial success of a human trial, involving 3 patients, for cystic fibrosis therapy is reported in J. Zabner et al., "Adenovirus-mediated gene transfer transiently corrects the chloride transport defect in nasal epithelia of patients with cystic fibrosis", Cell 75 (1993), 207-16. A trial that cured hemophilia in dogs is M.A. Kay et al., "In vivo gene therapy of hemophilia B: Sustained partial correction in factor IX-deficient dogs", Science 262 (1993), 117-9, 29-30. A trial in rabbit knee joints looking at future gene therapy for treatment of arthritis is G. Bandara et al., "Intracellular expression of biologically active interleukin 1-receptor-antagonist protein by ex vivo gene transfer", PNAS 90 (1993), 10764-8. A study on gene marking to follow bone marrow transplants is Lancet 342 (1993), 1134-7.

The ethical uses of germ-line gene therapy are discussed in N.A. Wivel & L. Walters, "Germ-line gene modification and disease prevention: Some medical and ethical perspectives", Science 262 (1993), 533-8. Above all they call for increased public discussion of the issue, something also called for in the Fukui Statement. The ethical issues of the slippery slope with regard to gene therapy are discussed in N. Holtug, "Human gene therapy: Down the slippery slope?", Bioethics 7 (1993), 402-19. A general comment on the slippery question of "How far we should go?", is in UNESCO Sources 51: 20-1. Comments on the UNESCO Bioethics Committee are in the Lettre of the French Bioethics Committee No. 29 (Dec), 2-3. On germ-line therapy, see New Scientist (27 Nov, 1993), 4.

The UK has decided not to introduce any new legislation regarding gene therapy; Nature 366 (1993), 194. In the US, the FDA is clarifying its regulations and role in the regulation of gene therapy, and they are published in D.A. Kesler et al., "Regulation of somatic cell therapy and gene therapy by the Food and Drug Administration", NEJM 329 (1993), 1169-73; Biotechnology 11 (1993), 1514.

UCSF has been awarded a US$2.25 million grant over the next five years from the NIH to create a Gene Therapy Core Center, aiming to apply gene therapy; GEN (1 Nov 1993), 35. Another two such centres are being established in the USA. A method to use microencapsulated cells for delivery of genes is reported in JAMA 270 (1993), 2119. A method to increase the delivery of drugs across skin using electroporation has been developed; PNAS 90 (1993), 10504-8.

An easy to read account of a recent trial where the patient's genes are mutated in efforts to combat cancer is Scientific American (Oct 1995), 9-11. A conference review on the promise of altering tumour suppressor genes by gene therapy to control cancer is GEN (15 Oct 1993), 1, 3. Also on gene therapy and cancer, Science 262 (1993), 32-3; JAMA 270 (1993), 2089-93, 2414,2416.

The Ministry of Health and Welfare in Japan has announced members of the Ethics Committee to assess applications for gene therapy; Nature 367 (1994), 399, 502. The Ministry of Education has just released their guidelines also, and will have a separate committee (with overlapping members). In university hospitals drugs already need the approval of both ministries, and so will gene therapy. One gene therapy protocol has been approved by Niigata University, and several other proposals are under consideration by other university committees, after which approval must be given by both ministries. The University of Tsukuba gene therapy working group, of which I was a member, has just announced guidelines for researchers here in Tsukuba also. They are basically those of the NIH in the USA, with some local modifications and one or two extra requirements over the national guidelines. There has been reasonable interest in the results of our surveys of attitudes to gene therapy in Japan and other countries in the International Bioethics Survey. A variety of Japanese newspapers have run stories on the increased support for gene therapy shown in the 1993 survey (see the EEIN (Nov 93)).

The UK Gene Therapy Advisory Committee (GTAC) has 16 members, including lay members. It will review all proposals for gene therapy on human subjects in the UK, and advise on the ethical acceptability of such research. An opinion from the French National Ethical Consultative Committee for the Life and Health Sciences approving somatic cell gene therapy with general notes is in IDHL 44 (1993), 753. In the December 1993 meeting of the NIHRAC another 9 gene therapy trials were approved, Biotechnology 12 (1994), 24-3. Five were for cancer, three for genetic diseases and another for AIDS. Another proposal was rejected .

A review is M.P. Colombo & G. Forni, "Cytokine gene transfer in tumor inhibition and tumor therapy: where are we now?", Immunology Today 15 (1993), 48-51. It includes a number of mouse studies and some future research. A report from the Second International Conference on the Gene Therapy of Cancer suggesting that cancer patients will be the first major group to benefit from gene therapy is in GEN (15 Jan1994), 1, 14-5. It describes the growing research being conducted by companies, and the variety is too great to report here.

Another report looks at the company GeneMedicine which is attempting to develop packaged vectors for delivery like drugs; GEN (15 Jan1994), 5, 8. Collaboration between two companies, Chiron and Viagene in gene therapy research is discussed in Biotechnology 12 (1994), 16, 18. A paper on the results of transfer of cystic fibrosis gene to airway epithelia of primates and rats is in Nature Genetics 6 (1994), 75-83. The results of the implantation of fibroblast cells containing the gene to express neurotrophin-3 resulted in prevention of the death of certain neurons, Nature 367 (1994), 368-71. Hepatic (liver) gene therapy is described in PNAS 90 (1993), 11548-52.

A report on the successful direct transfer of a gene for transplantation antigen HLA-B7, by liposomes by direct injection into tumours is in GEN (1 Jan 1994), 33. In all five patients an immune response was generated, but tumour regression was observed only in one patient in these preliminary trials at the University of Michigan.

A general review of gene therapy and biotechnology is in Biotechnology 12 (1994), 42-5. A review looking at animal studies is J.N. Lozier & K.M. Brinkhous, "Gene therapy and the hemophilias", JAMA 271 (1994), 47-51. The long term in vitro survival of hematopoietic stem cells is reported in PNAS 91 (1994),, 350-4. A general review of research in DNA repair is Cell 76 (1994), 1-4.

The conclusions of a multidisciplinary group in Canada, Genethiq, on ethical issues in gene therapy are presented in french in IJB 4 (1993), 293-7. They look at the vulnerability of both children and parents at the time of a clinical trial, and the issue of long term consent given by the parents for their child. A Catholic view of genetic intervention, including rejection of germ-line therapy, is in Catholic Medical Quarterly 44:1 (Aug 93), 17-21. A paper calling for the development of national guidelines for germ-line gene therapy before international ones is A.L. Bonnicksen, "National and international approaches to germ-line gene therapy", Politics & Life Science 13 (Feb 1994), 1-11. She mainly considers preimplantation diagnosis as an example.

The UNESCO International Bioethics Committee discussed a draft report on gene therapy in September, Nature 371 (1993), 369. As one of the members of this committee, I would summarise the positions adopted in the 1994 report on gene therapy as: 1) encouragement of somatic cell gene therapy for any disease, 2) to deliberately not make somatic cell gene enhancement or germ-line gene therapy illegal, 3) to outlaw germ-line gene enhancement. These are liberal, and we can compare to the Council of Europe Draft Bioethics Convention, Article 16 prohibits modifications which would affect the human germ cell line and be transmitted to subsequent generations, although the Convention accepts possible future exceptions. The UNESCO draft report suggests we should not outlaw germ-line therapy or somatic cell enhancement. This position reflects the logic of obtaining international support and being independent of time.

In Japan the trial for ADA deficiency in Hokkaido University is still being debated, with the formation of a working group of the 7 overlapping members of the Ministry of Education and Ministry of health and Welfare committees; Nature 371 (1994), 464. They are requesting further information from the FDA in the USA, some of which is commercially sensitive. A mouse model of ADA transfer into B-lymphocytes is in PNAS 91 (1994),, 8875-9. The process for US gene therapy approvals is becoming streamlined as said in the last issue. The US RAC will be advisory to both the NIH Director and FDA, and all protocols for gene therapy will be directly submitted to the FDA, and they will forward copies to the NIH Office of Recombinant DNA Activities to determine whether full RAC review is needed; Gene Therapy Newsletter (Sept/Oct 1994), 1-2. On October 24 the Fourth Hiroshima Cancer Seminar was held on gene therapy of cancer, in which I participated in a panel discussion on bioethics and efficacy.

The UK Gene Therapy Advisory Committee has released Guidance on Making Proposals to Conduct Gene Therapy Research on Human Subjects, 20pp. A press release and details for researchers who wish to submit proposals are available from the secretary, Mr. A. Taylor, GTAC Secretariat, Dept. of Health, Wellington House, 133-135 Waterloo Rd, London SE1 8UG, UK. On germ-line gene therapy they recommend that in the absence of ways to assess the safety, "gene modification of the germ line should not yet be attempted." The committee requires information on: justification of the proposed research, and its scientific validity; assessments of the risks of harm and (where the research has a therapeutic purpose) the potential benefits, and their relative weight; the degree to which safety of subjects and third parties is taken into account in the design of the research; the criteria for recruitment and selection of subjects; the means of informing potential subjects - and their parents or guardians, in the case of children - and seeking appropriate consent. More French gene therapy centres are now funded, Nature 371 (1994), 550.

A 1994 Gallup poll in the UK reports up to 20% of people accepting enhancement gene therapy, which is much higher than 1993; Nature 371 (1994), 193. The Gallup poll asked people whether they would use genetic methods to affect "aggression", and in 1993 5% approved whereas 18% approved in 1994. The same result was found for "alcoholism", with "homosexuality" increasing from 4% to 10% and "good looks" from 2% to 5% approval. This is generally less than in the International Bioethics Survey. Papers on ethical issues include: Resnik, D. "Debunking the slippery slope argument against human germ-line gene therapy", J. Med. Phil. 19 (1994), 23-40.

The use of adenoviral vectors in rat for possible Parkinson's disease treatment is reported in Kaplitt, et al., "Long-term gene expression and phenotypic correction using adeno-associated virus vectors in the mammalian brain", Nature Genetics 8 (1994), 148-53. Also on adenoviral vectors see J. Exp. Med. 179: 1867-75; PNAS 91 (1994),, 6186-90; JBC 269: 11542-6. The vector is found ineffective in cystic fibrosis mouse and human trials in Grubb, B.R. et al. "Inefficient gene transfer by adenovirus vector to cystic fibrosis airway epithelia of mice and humans", Nature 371 (1994), 802-6. A general discussion of possible therapies for CF is NEJM 331 (1994), 672-3. Thalassemia treatment is discussed in NEJM 331 (1994), 574-8, 609-10; and muscle therapy in TIG 10 (1994), 301-2.

Reconstitution of the epidermis in pigs is reported in Vogt, P.M. et al. "Genetically modified keratinocytes transplanted to wounds reconstitute the epidermis", PNAS 91 (1994),, 9307-11. Genetic vaccination is discussed in Raz, E. et al. "Intradermal gene immunization: The possible role of DNA uptake in the induction of cellular immunity to viruses", PNAS 91 (1994),, 9519-23. On homologous gene transfer see PNAS 91 (1994),, 8527-31.

Potential AIDS treatment include Duan, L. et al. "Potent inhibition of human immunodeficiency virus type 1 replication by an intracellular anti-Rev single-chain antibody", PNAS 91 (1994),, 5075-9; see also PNAS 91 (1994),, 5932-6; JAMA 272 (1994), 423. A mouse model for Gaucher's disease therapy is Blood 83: 2737-48. The use of folate receptor to target genes to treat cancer is in Gene Therapy 1: 185-91. A system for differentiation of lymphohematopoietic cells from embryonal stem cell lines is in Science 265 (1994), 1098-1101. Those who wish to look at patent reviews and literature on gene therapy should see the Gene Therapy Newsletter, from Derwent Information Ltd., 14 Great Queen Street, London WC2B 5DF, UK.

A statement from representatives of European patient and consumer groups supporting the use of biotechnology in medicine and to produce new products is reproduced in BME 95 (Feb 1994), 3-4. They also support transgenic animal research for those goals.

The NIHRAC has called for faster review of gene therapy applications, Biotechnology 12 (1994), 356. Also in its March meeting another 6 proposals were approved (four for cancer, one for AIDS and one for alpha antitrypsin deficiency). With the extra time from streamlined review, they may be able to look at germ-line issues more. A paper calling for national approaches to regulate preimplantation diagnosis and gene therapy is A.L. Bonnicksen, "National and international approaches to human germ-line gene therapy", Politics & Life Science 13 (Feb 1994),39-50. Commentaries will be published in August about this paper.

A report on the use of gene therapy to treat hypercholesterolemia is M. Grossman et al., "Successful ex vivo gene therapy directed to liver in a patient with familial hypercholesterolaemia", Nature Genetics 6 (1994), 335-41, with a review by D. Weatherall on p. 325-6; Nature 368 (1994), 665. They report how part of her liver was removed, treated with the gene for the LDL receptor, the cells infused back into the liver, and the level of LDL in the blood dropped significantly, over the 18 months observation period reported in this paper. There is editorial comment in Nature Genetics 6 (1994), 323-4, which also discusses the book, Larry Thompson, Correcting the Code (Simon & Schuster, New York; US$23). The report is the longest study of gene therapy reported, though the ADA deficiency studies elsewhere in the USA have been working for a longer period. A general discussion of techniques in liver gene therapy is S.D. Rettinger et al., "Liver-directed gene therapy: Quantitative evaluation of promoter elements by using in vivo retroviral transduction",PNAS 91 (1994),, 1460-4. The success in dogs is M.A. Kay et al., "In vivo hepatic gene therapy: Complete albeit transient correction of factor IX deficiency in hemophilia B dogs", PNAS 91 (1994),, 2353-7.

The use of cancer vaccines for gene therapy featured at the 1994 BioEast conference in Washington DC;GEN (15 Feb 1994), 1, 20. It includes a discussion of new commercial developments. See also Nature 368 (1994), 495-6. More comments on methods to control human gene expression as therapy are in GEN (15 Feb 1994), 1, 19.

The use of a recombinant Fab antibody to treat RSV in lungs of mice is in PNAS 91 (1994), 1386-90. The use of polymers to add cell delivery is in S.R. Winn et al., "Polymer-encapsulated cells genetically modified to secrete human nerve growth factor promote the survival of axotomized septal cholinergic neurons", PNAS 91 (1994), 2324-8. The use of convection to deliver molecules to the brain is discussed in PNAS 91 (1994), 2076-80.

A paper on the ethics of gene therapy is JRSM 87 (1994), 302-4.

The ultimate goal for gene therapy is targeted injectable gene vectors, and a review of companies researching this is GEN (15 April 1994), 8-9, 29. It also reviews general gene therapy research. Liposome research is reviewed in GEN (15 April 1994), 24-5. A new gene therapy company, Magenta Corp. has been formed as a subsidiary of Microbiological Associates, to produce materials for gene therapy; GEN (1 April 1994), 1, 20-1.

A gene therapy trial to treat HIV has begun at the Uni. California, San Diego; GEN (1 April 1994), 27. Reviews include, E. Gilboa & C. Smith, "Gene therapy for infectious diseases: the AIDS model", TIG 10 (1994), 139-144; T. Friedmann, "Gene therapy for neurological disorders", TIG 10 (1994), 210-4. Papers on animal models include: S.-H. Chen et al., "Gene therapy for brain tumors: Regression of experimental gliomas by adenovirus-mediated gene transfer", PNAS 91 (1994),, 3054-7; J.C. Perales et al., "Gene transfer in vivo: Sustained expression and regulation of genes introduced into the liver by receptor-targeted uptake", PNAS 91 (1994), 4086-90; D.M. Frim et al., "Implanted fibroblasts genetically engineered to produce brain-derived neurotrophic factor prevent 1-methyl-4-phenylpyridinium toxicity to dopaminergic neurons in the rat", PNAS 91 (1994), 5104-8 (a model of Parkinson's); K. Zatloukal et al., "In vivo production of human factor VIII in mice after intrasplenic implantation of primary fibroblasts transfected by receptor-mediated, adenovirus-augmented gene delivery", PNAS 91 (1994), 5148-52 (for hemophilia A); and a model for treatment of a failing heart, Science 264 (1994), 582+, 507-8.

Steven Rosenburg has received the grant money that was withheld in late 1992 following his speedy use of gene therapy, Nature 369 (1994), 598. Difficulties in the establishment of a UK gene therapy centre are in Science 264 (1994), 895. A pharmaceutical company in France, Rhone-Poulenc, has decided to set up groups to work on gene therapy, Nature 369 (1994), 92.

The proposed UNESCO guidelines on gene therapy is further discussed in D. Macer, "UNESCO Bioethics Committee and International Regulation of Gene Therapy", Gene Therapy Newsletter 4 (1994), 4-5; and in Lancet 344 (1994), 946. The Group of Advisors on the Ethical Implications of Biotechnology of The European Commission have made public (in a press release on 13 Dec 1994) their opinion on gene therapy, EBN 192 (1995), 1-2; Nature 372 (1995), 716. The say no proposal for germ-line gene therapy is even being contemplated, but see next paragraph. A summary paper is Cohen- Haguenauer, O. "Regulation of gene therapy in Europe: a current statement including reference to US regulation", Eur. J. Cancer 30: 1193-201.

A symposium on germ-line gene therapy is in Politics & Life Sciences 13: 217-48. It includes commentaries from many writers (Cook-Degan, Blank, Chadwick, Fletcher, Knoppers & LeBris, Mauron, Shapiro, Wertz, Winston, Byk, Kielstein, Macer, Bonnicksen - most of whom receive the EEIN), and covers a wide range of views on international versus national regulation. The NIH has again been urged to study fetal gene therapy and germ-line gene therapy, Science 266 (1994), 490, 1631; Biotechnology 13 (1995), 18-9. Several papers which open up the technical possibility of engineering sperm are: Brinster, R.L. & Zimmerman, J.W. "Spermatogenesis following male germ-cell transplantation", PNAS 91 (1994),, 11298-302; Brinster, R.L. & Avarbock, M.R. "Germline transmission of donor haplotype following spermatogonial transplantation", PNAS 91 (1994),, 11303-7, 11287-9; Science 266 (1994), 1482. Also on the need for public review of gene therapy, Biotech 12: 1065-6.

Gene therapy to treat baldness is being developed, and a review is GEN (Dec 1994), 12, 35. Is baldness a disease? In a question in the International Bioethics Survey in India we asked people to list genetic diseases, and baldness was one of the top 4-5 listed.

A financial study by Frost and Sullivan suggests that the gene therapy market will be worth US$2.6 billion by the year 2000; EBN 186 (1994), 2-3. They predict half of this will be for cancer therapies. Also on the business prospects, GEN (Dec 1994), 16. A new company formed from the collaborative agreements of Rhone- Poulenc and 14 different institutes is called RPR Gencell, and is based in the USA; EBN 189 (1994), 1-2; New Scientist (19 Nov 1994), 4; GEN (Dec 1994), 1, 41; Nature 372 (1995), 210; Science 266 (1994), 1151. Other institutes may join, the benefit is for Rhone-Polenc to have first look for patents. France is also coordinating gene therapy at a government level, Lancet 344 (1994), 1494; Nature 372 (1995), 397. In the USA vector centers are being formed to speed up clinical trials, Nature 372 (1995), 306; Science 266: 1326.

Papers on the use of sensitivity genes as cancer therapy include: Sorscher, E.J. et al. "Tumor cell bystander killing in colonic carcinoma utilizing the Escherichia coli DeoD gene to generate toxic purines", Gene Therapy 1: 233-8;Gene Therapy Newsletter 4: 1-2. This approach involves the introduction of an enzyme into tumor cells that confers sensitivity to a normally nontoxic chemical, such as ganglovir, so that cells with the enzyme (e.g. Thymidine kinase) die. A paper reporting the sensitization of tumor cells by radiation allowing better targeting is Cancer Research 54: 4266-9. An alternative to genes is a technique of burning out brain tumours by interventional magnetic resonance imaging, New Scientist (17 Dec 1994), 23.

Possibilities for gene therapy treatment of growth hormone abnormalities include: Gene 145: 305-10; Heartlein, M.W. et al. "Long-term production and delivery of human growth hormone in vivo", PNAS 91 (1994),, 10967-71. The stable delivery of erythropoietin is reported in PNAS 91 (1994),, 11557-61. New hemoglobins are expressed in mice is McCune, S.L. et al. "Recombinant human hemoglobins designed for gene therapy of sickle cell disease", PNAS 91 (1994),, 9852-6. A review of several trials underway on HIV is JAMA 272 (1994), 1235-6.

Other technical papers include: use of adenoviral vectors: Podsakoff, P.G. et al. "Efficient gene transfer into nondividing cells by adeno-associated virus-based vectors", J. Virology 68: 5656-66; PNAS 91 (1994), 8802-6; PNAS 91 (1994), 10183-7; (in the December 1994 issue of Gene Therapy Newsletter 5 there were 43 papers with adenovirus vectors); using vaccinia vectors, Lee, S.S. et al. "Intravesical gene therapy: in vivo gene transfer using recombinant vaccinia virus vectors", Cancer Research 54: 3325-8; on cystic fibrosis, Science 266 (1994), 1705-8. Organ targeting systems are discussed in EBN 191 (1994), 1-2; Science 266 (1994), 1373-6; and regulation of gene expression in Gene Therapy Newsletter 5 (1994), 1-2.

In Japan Hokkaido University Gene Therapy Committee approved an emergency gene therapy protocol for ADA deficiency. It was submitted to the Ministry of Health and Welfare committee who are still to pass a decision. A newspaper report from Prof. F. Takaku on the committee has suggested the safety data that were submitted were insufficient; Yomiuri Shimbun (5 Sept 1994), 1, 30. The debate is whether the treatment can be approved soon because the patient may die. An early report is Nature 370 (1994), 243.

The attempt to correct cystic fibrosis by human gene therapy is reported in R.G. Crystal et al., "Administration of an adenovirus containing the human CFTR cDNA to the respiratory tract of individuals with cystic fibrosis", is Nature Genetics 8 (1994), 42-51, 8-9. They found no adverse effects after 6-12 months follow-up with the trial, and suggest it may correct the mutation in the airway epithelia.

A reduction in the number of reviews for gene therapy proposals in the USA will occur later in the year, with the RAC only EEIN cases which are thought to have particular problems, Science 265 (1994), 599; HGT 5 (1994), 665-6. An explanation of the 1993 RAC guidelines is in HGT 5 (1994), 399-407. A general history of gene therapy is in HGT 5 (1994), 469-80. A German report is K. Bayertz et al., "Summary of "Gene transfer into human somatic cells. State of the technology, medical risks, social and ethical problems: A report", HGT 5 (1994), 465-8. Comments on the British gene therapy center that is facing an uncertain future is Science 265 (1994), 303; BMJ 308 (1994), 1456.

A discussion of gene therapy ethics and a SCOPE Note 24 on "Human Gene Therapy" is in KIEJ 4: 63-83. A recent book is Kenneth W. Culver, ed., Gene Therapy. A Handbook for Physicians (New York: Mary Liebert 1994). A rejection of germ-line gene therapy is HGT 5 (1994), 127-8, 151-2; and a debate over enhancement is in Lancet 344 (1994), 316-7. "Gene therapy and genetic alteration" from the Canadian Royal Commission on New Reproductive Technologies, chapter 29, is in HGT 5 (1994), 603-14.

A newsletter on Gene Therapy Newsletter has begun, enquiries and sample copies can be obtained from Rumana Huq, Managing Editor, Derwent House, Derwent Information Limited, 14 Great Queen Street, London WC2B 5DF, U.K (Fax Int+44-71-344-2911). It is 24 pages per issue, monthly, and is especially designed for company researchers. It scans 1100 biomedical journals and patents from 36 issuing authorities for reviews of news in gene therapy. It will include some news, and ethics coverage, (D.M. is one of the editorial board members), but is mainly scientific in focus. Gene therapy is greatly expanding and there are numerous patents being sought.

The NIH RAC approved the first naked DNA vaccine trial, for patients with metastatic colorectal cancer at the University of Alabama; GEN (15 June 1994), 9. They also approved a lung cancer gene therapy trial, despite the concern that a new viral vector might cause pneumonia in patients dying of lung cancer; J. Natl. Cancer Institute 86: 964-5. Company news is in Biotechnology 12 (1994), 561-2; and on bigger vectors, pp. 586-91.

Some recent technical papers are: on inhibition of HIV replication, PNAS 91 (1994),, 5075-9; on adenovirus transfer into hematopoietic progenitor cells, J. Exp. Med. 179: 1867-75; on folate receptor mediated DNA transfer into cells, Gene Therapy 1: 185-91. A patent has been claimed for adenovirus vectors to transfer foreign genes into cells of the central nervous system. A delivery system using sugar coated magnetic particles into the brain is discussed in New Scientist (13 Aug 1994), 16; Neurosurgery (April), 777+. A summary of approaches to treating AIDS by gene therapy is HGT 5 (1994), 149-50; and cancer, HGT 5 (1994), 1-2. Also on general gene therapy progress, JAMA 271 (1994), 1813-4, 272: 257-8; TIBTECH 12 (1994), 109-13; HGT 5 (1994), 281-2; Lancet 343 (1994), 1507-8; 344: 257; Science 264 (1994), 1850; NEJM 331 (1994), 39-41, 49-50.

The results of a pig trial are in T. Ohno et al., "Gene therapy for vascular smooth muscle cell proliferation after arterial injury", Science 265 (1994), 781-4; with a review pp. 738. A report in Gene Therapy (Sept) describes an intracellular technique for knocking out the gene erbB2, a growth factor receptor that is overexpressed in some cancers. They used an ovarian cell line. Other animal trials include: PNAS 91 (1994), 6088-92, 6196-200, 7252-6; HGT 5 (1994), 283-93 (+many others) lung transfer in rhesus monkeys, HGT 5 (1994), 3-10.

The report of the Group of Advisors on Ethical Implications of Biotechnology of the European Commission, report on gene therapy (EJAIB 5: 20) is reproduced in BME 104 (Jan 1995), 4-6.

A paper on the limits of ethical genetic intervention is Agar, N. "Designing babies: morally permissible ways to modify the human genome", Bioethics 9 (1995), 1-15. He attempts to use a different argument to the therapeutic/eugenic distinction that some have used, and supports much of what is called eugenics. He sees life goals of persons as one of the major concerns. Another philosophical paper on the subject is Persson, I. "Genetic therapy, identity and the person-regarding reasons", Bioethics 9 (1995), 16-31. It takes the common sense view that even if a future person does not exist, they still have interests. It considers "Person-regarding" reasons, which concern the identity of future persons. It appears the philosophy has caught up with what most people believed.

Religious aspects are discussed in Archer, L. "Gene therapy in catholic thought", IJB 5 (1994), 229-33 (in English); Dinechin, O. de "Positions de l'Eglise catholique romaine sur la therapie genique", IJB 5 (1994), 235-9. The Catholic view may be open to some enhancement engineering under some circumstances.

On 1 February, the Ministry of Education, Science and Culture's gene therapy committee approved the proposal by Prof. Yukio Sakiyama, to treat ADA deficiency in a 4 year old boy at the University of Hokkaido, Japan. The proposal was filed in August, 1994, and it was approved at the third meeting of this committee considering it. It was approved by the Ministry of Health and Welfare's gene therapy committee on the 6th. The trial using ex vivo transfer to lymphocytes should be underway in spring; Japan Times (2 Feb, 1995), 3; Nature 373 (1995), 464.

At the start of 1995, there were 98 gene transfer and therapy protocols approved in the USA,Gene Therapy Newsletter 6: 1-2. There are also a growing number in Europe and Asia, in addition to the Japanese trial. In the USA, a phase II clinical trial, the first one, for intramuscular injection of HIV-IT (V) by Viagene is beginning Gene Therapy Newsletter 6: 2-3. About 190 HIV positive patients will be enroled at up to 15 clinical sites in the USA. It will be a placebo-controlled study. The Retrovector(r) targets the env and rev genes of HIV-1 to healthy non-HIV infected cells, which will then express the proteins. This is expected to make a cytotoxic T-lymphocyte response, which is different to the antibody response seen with protein vaccines.

Techniques for cancer gene therapy are discussed in Biotechnology 13 (1995), 127-31; Lancet 344 (1994), 1631; Nature 372 (1994), 642-5; Rooney, C.M. et al. "Use of gene-modified virus-specific T lymphocytes to control Epstein-Barr-virus-related lympho-proliferation", Lancet 345 (1995), 9-13; also p.53. Successful trials for targeting in arterial disease are in, Chang, M.W. et al. "Cytostatic gene therapy for vascular proliferative disorders with a constitutively active form of the retinoblastoma gene product", Science 267 (1995), 518-22 Lancet 344 (1994), 1653-4; 345: 248. Increased platelet counts following HST-1 gene transfer in mice have been found, PNAS 91 (1994), 12368-72. A method to increase uptake of liposomes is reported in PNAS 91 (1994), 12669-72.

Tissue engineering is discussed inGEN (1 Jan 1995), 1, 44. Hematopoietic stem cells have been isolated, Science 267 (1995), 104-8.

In mid-April 1995 the two regulatory committees of the Japanese government (Ministry of Education, Science and Culture, and the Ministry of Health and Welfare) on gene therapy will consider approving an application by a Kyushu hospital for trials of gene therapy against AIDS using a U.S. company vector. The Kumamoto Medical University gene therapy committee held an open public meeting presenting the trial, and announcing it would seek approval of the central government committees to commence clinical trials. The first gene therapy trial approved in Hokkaido also used a vector developed overseas (for ADA deficiency); Asahi Shimbun (31 March 1995), 34. A somewhat out of date background on Japan's first gene therapy trial is Nature Medicine 1 (1995), 9; Science 267 (1995), 967. Seven Japanese pharmaceutical companies have joined with the government to set up a company to make gene therapy vectors, Nature 374 (1995), 394.

The procedures required for gene therapy approval in the UK are reproduced in BME 105 (Feb), 8-11. Although Viagene could get approval for their phase II clinical trial from the NIH RAC (Recombinant Advisory Committee), there are signs that industry could have some problems in getting trials accepted, Nature 374 (1995), 202.

The NIH has won a patent in the US on the general techniques of gene therapy, Nature 374 (1995), 393. The first inventor is named as W. French Anderson, and it covers all ex vivo manipulations in which malfunctioning human cells are genetically altered to produce therapeutic levels of protein outside the body and then replaced. There is much controversy over the broad nature of it.

A paper arguing that human genetic enhancement cannot be effectively stopped is Gardner, W. "Can Human Genetic Enhancement Be Prohibited," J. Med. & Phil. 20 (1995), 65-84. The position statement of the Council for Responsible Genetics on Human Germ-line Manipulation is reproduced in IJB 5 (1994), 311-5. A mouse study finds genes can transfer from mother to fetus, New Scientist (4 March, 1995), 16; Nature Genetics 9 (1995), 243+. A further comment (see last issue) reviewing catholic church views on gene therapy is Grima, G. "Gene therapy and the Catholic Church", IJB 5 (1994), 321-6.

More discussion of the recently approved phase II clinical trials of Viagene's anti AIDS vaccine is GEN (15 Feb 1995), 1, 21. A review in general for AIDS therapy is Bridges, S.H. & Sarvar, N. "Gene therapy and immune restoration for HIV disease", Lancet 345 (1995), 427-32. A review of technical progress in cancer treatment is GEN (1 March 1995), 8-9; and on company projects to develop vaccines against HIV and cancer, GEN (15 Feb 1995), 6. A review on the use for brain disorders is Martin, J.B. "Gene therapy and pharmacological treatment of inherited neurological disorders", TIBTECH 13 (1995), 28-35. A study has found a method to keep transplanted neurons alive in the brain, New Scientist (14 Jan, 1995), 14.

A new book is Lever, A.M.L. & Goodfellow, P. Gene Therapy (Churchill Livingstone, 1995, as part of the British Medical Bulletin series). On the general use of gene therapy, Nature Medicine 1 (1995), 1, 15-7. The use of adenovirus vectors for treating cystic fibrosis is discussed in Nature 374 (1995), 96; Nature Medicine 1 (1995), 39+; Nature Genetics 9 (1995), 126+; New Scientist (7 Jan, 1995), 6.

The guidelines for approval of gene therapy in the UK are listed in BME 105 (1995), 8-11. In early June the second trial for cystic fibrosis gene therapy began in the UK, EBN 202 (1995), 5; Nature Medicine 1 (1995), 182. It includes women, who have the risk of germ-line change because unlike men they are not sterile. However, so do many other persons with other diseases in gene therapy trials and it has never been reported. A paper looking at the regulation in general is Ventura, M. "Rules for gene therapy. The secularity of the state and the challenge of bioethics", JLME 23 (1995), 49-54.

A paper on genetic enhancement is Gardner, W. "Can genetic enhancement be prohibited?", J. Med. & Phil. 20 (1995), 65-84. On the ethics of genetic engineering, Human Gene Therapy 6 (1995), 3-4; Nature Medicine 1 (1995), 181. A review of the NIH-RAC is discussed in Biotechnology 13 (1995), 431-2; Gene Therapy 2 (1995), 3; Human Gene Therapy 6 (1995), 1-2; Nature Medicine 1 (April 1995). In Japan a program of 15 trials until the end of 1996 is envisaged, and a report on the first trial (which is still to be announced as started) is Nature Medicine 1 (1995), 188.

A discussion over whether the US Patent No. 5,399,346 - Gene Therapy, will be challenged is GEN (15 May 1995), 22-3; Science 267 (1995), 1899; NS (1 April, 1995), 4. The patent is held by NIH and Gene Therapy Institute, a company, which could make arrangements more commercial than in the case of the Cohen-Boyer genetic engineering patent held by Stanford University. It covers ex vivo manipulated cells, so direct gene transfer may be exempt.

An interesting patent application is announced from AntiCancer Inc., a San Diego company, which has developed a liposome based method to stop hair graying. It was announced on 6 March, and was originally developed for use among patients receiving anti-cancer treatment.They plan to insert the gene controlling hair colour into the liposomes for transfer. General comments on commercial agreements for gene therapy companies are in GEN (15 May 1995), 1, 15; Biotechnology 13 (1995), 429-31. Chiron is expanding gene therapy research, Nature 375 (1995), 8. In Japan, the scheme announced last issue is discussed in Nature Medicine 1 (1995), 291.

General comments on gene therapy are in Lancet 345 (1995), 739-40; Nature 375 (1995), 545-6; Science 267 (1995), 1411, 1588, 1889, 268 (1995), 627; Gene Therapy 2 (1995), 81-3. On DNA vaccines, JAMA 273 (1995), 1403-4; PNAS 92 (1995), 1744-8; Nature Medicine 1 (1995), 221-5. New research includes: sickle cell disease, PNAS 92 (1995), 3014-8; anti-cancer, PNAS 92 (1995), 1411-5, 2577-81, 2889-93; Nature Medicine 1 (1995), 309-20; NS (25 March, 1995), 16; adrenoleukodystrophy, PNAS 92 (1995), 1674-8; insulin, PNAS 92 (1995), 3293-7; and long term lysosomal enzyme delivery by fibroblasts, Nature Medicine 1 (1995), 353-7. Prospects for boosting cardiac contractibility by genes are assessed in NEJM 332 (1995), 817-8; and on muscle gene transfer, TIG 11 (1995), 163-5. There three full journals concentrating on the science of gene therapy, Human Gene Therapy (USA), and Gene Therapy (London), and Cancer Gene Therapy (USA).

Gene transfer methods are discussed in GEN (1 April 1995), 1, 17, 25; and ribozymes in Nature Medicine 1 (1995), 277-8, 300-2, also. pp. 210-1, 275-6. Jumping genes in NEJM 332 (1995), 941-4; NS (18 March, 1995), 16.

The results of the International Bioethics Survey related to gene therapy are included in a paper, D. Macer et al. "International perceptions and approval of gene therapy", Human Gene Therapy 6 (1995), 791-804. The results of the survey show strong support in all countries surveyed, also looking at eugenics, and education.

A description of the review process underway on the functions of the NIH RAC is Nature Medicine 1 (1995), 497. The reviewers have suggested streamlining of the review process, Nature 375 (1995), 713; as also suggested by former members of the RAC, Science 268 (1995), 1261; Gene Therapy Newsletter 13 (1995), 1-3. It was suggested that only new vectors be reviewed by the RAC, to avoid duplication of the FDA review. The report of the European Group of Advisors on Ethical Implications of Gene Therapy is in WHO Int. Digest Health Legislation 46 (1995), 271+. There is also a paper on regulation in Europe, Cohen-Haguenauer, O. "Overview of regulation of gene therapy in Europe: A current statement including reference to US regulation", Human Gene Therapy 6 (1995), 773-86. Letters on the safety of retroviruses are in Science 269 (1995), 417; also J. Mol. Med. 73 (1995), 4, B11.

The US FDA approved the export to Japan of a retroviral vector produced by Genetic Therapy Inc. and the NIH to treat ADA deficiency. It was used in Japan's first gene therapy trial in Hokkaido University; Nature 376 (1995), 202. A comment on Japan's gene therapy is Hoshino, K. Gene therapy in Japan: Current trends", CQHE 4 (1995), 367-70. The funding of a joint FDA/NIH clinical gene therapy databank is delaying expansion of the databank, which includes over 600 patients, Science 269 (1995), 467. There are still those who would say there is slow progress, Biotechnology 13 (1995), 714.

A review of the British gene therapy company, Therapeutic Expression Systems (Keele, Staffs) is Nature Medicine 1 (1995), 502-3. They have been granted a European patent on the use of locus control regions to direct expression of therapeutic genes in a tissue specific manner. A critique of the broad gene therapy patent awarded to the NIH (see EJAIB 5 (1995), 108) is Nature Medicine 1 (1995), 392. Japan is unlikely to recognise the US NIH broad gene therapy patent, should they apply in Japan, Nature Medicine 1 (1995), 500-1. GATT allows exceptions on diagnostic, surgical or therapeutic inventions for use in animals or humans.

Sandoz Ltd has signed an agreement to acquire Genetic Therapy Inc., GEN (August 1995), 1, 8; EBN 204 (1995), 3-4. They don't expect revenue for at least 5 years, but it promises much in the future... Up to FF1 billion will be spend on setting up gene therapy companies and boosting sequencing projects up to the year 2000, by the French government, EBN 203 (1995), 1. Boehringer Mannheim has signed two deals with American companies (Sequana Therapeutics and osteoporosis, and Gene Medicine in the field of cancer) valued at US$150 million, EBN 205 (1995), 3.

A paper reporting gene therapy of hair follicles is Li, L.N. & Hoffman, R.M. "The feasibility of targeted selective gene therapy of the hair follicle", Nature Medicine 1 (1995), 705-6. They use liposome targetting in mice, and this technique is the subject of a patent claim, reported earlier in EJAIB. A paper looking at germ-line therapy is Rubenstein, D.S. et al. "Germ-line therapy to cure mitochondrial disease: Protocol and ethics of in vitro ovum nuclear transplantation", Cambridge Quarterly of Healthcare Ethics 4 (1995), 316-39. In this paper they make a nine step protocol for germ-line therapy, and ethical evaluation, and call for comments. In this issue there are several other papers under the theme of "Designs on Life: Choice, Control , and Responsibility in Genetic Manipulation."

Promising results from two laboratories with the expression of a dystrophin gene and removal of muscular dystrophy symptoms in mice is reported in Wells, D.J. et al. "Expression of human full-length and minidystrophin in transgenic mdx mice: implications for gene therapy of Duchenne muscular dystrophy", Human Molecular Genetics 4 (1995),1245-50; Phelps, S.F. et al. "Expression of full-length and truncated dystrophin mini-genes in transgenic mdx mice", Human Molecular Genetics 4 (1995), 1251-8. Up to 20-30% expression had very good results.

A mouse model for hemophilia B therapy is Alexander, M.Y. et al. "Circulating human factor IX produced in keratin-promoter transgenic mice: a feasibility study for gene therapy of haemophilia B", Human Molecular Genetics 4 (1995), 993-9. A mouse study for treatment of metastatic cancer is Nature Genetics 10 (1995), 430-5; and a review of two phase I cancer trials that joined the 130 gene therapy trials world-wide is GEN (July 1995), 1, 31. A review on gene therapy for vaccination is Gene Therapy 2 (1995), 173-80; on vascular disease, FASEB J. 9 (1995), 843-51; PNAS 92 (1995), 5266-72; on mitochondrial disorders, Gene Therapy 2 (1995), 311-6; on enzyme delivery for anticancer therapy, Gene Therapy 2 (1995), 235-44; on gene therapy into injured carotid arteries, Circulation 91 (1995), 2407-14; and on gene therapy using retroviral delivery into the lungs of fetal sheep, Gene Therapy 2 (1995), 344-50. The use of gene transfer studies to study the plasminogen/plasmin system is reviewed in FASEB J. 9 (1995), 934-8; and a paper reporting possible use in transfer to primary chronic granulomatous disease monocytes is Lancet 345 (1995), 92-3. A series of reviews on gene therapy are in Institute of Laboratory Animal Resources News 36 (No. 3-4, 1994), 45-74. On gene therapy and HIV from the UCSF trial, GEN (1 June 1995), 4.

The use of encapsulated cell therapies, which can include genetically modified cells, is a growing area for commercial interest, GEN (July 1995), 1, 12-3.

Two new books on gene therapy are: Vos, J.M.H., ed., Viruses in Human Gene Therapy, Chapman & Hall 1995, 214pp., 39 pds. which includes chapters on adenoviruses, retroviruses, herpesviruses, poxviruses, and modifications of these; and Dickson, G., Molecular and Cell Biology of Human Gene Therapeutics, Chapman & Hall 1995, 214pp.403pp., 60 pds. Both are technical volumes with little discussion of ethical issues specifically, but some comparison of the safety of different vectors and procedures. The Dickson volume contains about 3 times more information that the former book, and includes more Europeans and a Japanese contributor. Both are reasonably up-to-date in a fast moving field.

At last the long-awaited scientific papers showing the first disease to be treated by gene therapy, ADA deficiency have been published: Bordignon, C. et al. "Gene therapy in peripheral blood lymphocytes and bone marrow for ADA- immunodeficient patients", Science 270 (1995), 470-5; Blaese, R.M. et al. "T lymphocyte-directed gene therapy for ADA- SCID: Initial trial result after 4 years", Science 270 (1995), 475-9; and a review of progress, Science 269 (1995), 1050-5;EBN 210 (1995), 2-3. In September 1995 the number of approved gene therapy trials in the RAC-FDA of the USA became 100; with another 25 gene transfer trails. In the consolidated process of review, 9 of 13 protocols were sent directly to the FDA without RAC approval; Gene Therapy Newsletter 15 (Oct 1995), 1-3. The total for diseases reached, 63 for cancer, 22 for genetic disorders, 12 for HIV infection, 1 for peripheral vascular disease, and 2 for autoimmunity. The future of the RAC is uncertain, Science 270 (1995), 1659.

Also on the progress of gene therapy, SA (Sept 1995), 124-8; but two examples with no benefit yet, from myoblast therapy in muscular dystrophy and cystic fibrosis, NEJM 333 (1995), 823-31, 832-8, 871-3; Newsweek (16 Oct 1995), 46-8; Crystal, R.G. "Transfer of genes to humans: Early lessons and obstacles to success", Science 270: 404-10; Lancet 346 (1995), 959. From 10-13 Sept, 1995, there was an international gene therapy meeting hosted by Kunio Yagi in Inuyama, and Nagoya, which discussed many of the hurdles to success. A statement on gene therapy research was released, which will be reproduced in a later issue of EJAIB.

Two reviews are: Macer, D. Paper Review: "Designing babies: morally permissible ways to modify the human genome", Gene Therapy Newsletter, 9 (1995), 7; Macer, D. Paper Review: "Can human genetic enhancement be prohibited?", Gene Therapy Newsletter, 11 (1995), 6-7. A paper looking at enhancement is Parens, E. "The goodness of fragility: On the prospect of genetic technologies aimed at the enhancement of human capacities", KIEJ 5 (1995), 141-54. Science magazine also includes some discussions on genetics and policy on the Internet; Science 270 (1995), 359:

http://www.aaas.org/science/science.html

The NIH has picked three national gene vector laboratories, at Indiana, Michigan and Pennsylvania Universities, Science 270 (1995), 751-2. The French company Rhone-Poulenc Rorer and Applied Immune Systems have signed an agreement to plan for a merger, and they will develop gene and cell therapy; EBN 210 (1995), 2-3. Hoechst Marion Roussel and Cell Genesys have made an agreement in gene therapy collaboration, EBN 209 (1995), 3.

A paper reporting creation of a mouse model and then gene therapy to repair the disease is Paszty, C. et al. "Lethal alpha-thalassAEMia created by gene targeting in mice and its genetic rescue", Nature Genetics 11 (1995), 33-9. The use of attenuated Shigella for gene delivery and immunisation is reported in Science 270 (1995), 299-303. Long-term expression of genes in mice following adenoviral mediated gene transfer as an immunotherapy is Nature Genetics 11 (1995), 191-7; and long-term expression of erythropoietin in rats, PNAS 92 (1995), 8055-8. Adenoviruses were also shown to be successful to transfer to retina also, PNAS 92 (1995), 7700-4.

A new method to transport peptides into cells called cell-permeable peptide import uses a small peptide signal as a link to allow transport of proteins into cell, GEN (15 Sept 1995), 1, 12; and another method is ultrasound, Mitragotri, S.; et al. "Ultrasound-mediated transdermal protein delivery", Science 270 (1995), 850-3.

A paper using organoids to produce erythropoietin in mice is Gene Therapy 2 (1995), 411-7. The use of cell implants for vascular injuries is reported in PNAS 92 (1995), 8130-4. On inducible gene targeting in mice, Science 270 (1995), 1427-9.

A series of papers on enhancement are Gillies, J.D. et al. "The mark 2 human genome", BMJ 311 (1995), 1669-75, 76. Arguments against germ-line therapy are discussed in GenEthics News 9 (Nov/Dec 1995), 6-7. The end of year issue of BMJ included discussion on the possible improvements to human beings, such as putting the brain in the chest and other adaptations which we could consider "enhancement" genetics. A review of the proposed germ-line gene therapy protocol reported in CQHE 4 (1995), 316-39, by D. Macer is Gene Therapy Newsletter 17 (1995), 12, 15.

A report on how to provide patients easy to understand information is UK Gene Therapy Advisory Committee, "Writing information leaflets for patients participating in gene therapy research", BME 112 (1995), 18-21. A review of the UK system is A.J. Taylor, & J. Lloyd, "The role of the Gene Therapy Advisory Committee in the oversight of gene therapy research in the UK", Biologicals 23 (1995), 1, 37-8. Canadian regulation is reviewed in A. Ridgway, "Regulation of gene therapy: the Canadian approach. Ethical and regulatory issues in Canada", Biologicals 23 (1995), 1, 31-6. A news report from Japan is Nature Medicine 1 (1995), 856; and guidelines have been made which clarify many of the material standards, Nature 378 (1995), 327. Commercialization of gene therapy is discussed in TIBTECH 13 (1995), 290-4.

During 1995 the US RAC approved 38 gene therapy trials, including 24 for cancer, 5 for genetic disorders, 8 for HIV infection and 1 for autoimmune disease, bringing the total to 112 gene therapy trials, and 27 gene marking trials, Gene Therapy Newsletter 17 (1995), 1-3. Also in the Newsletter is the executive summary of the ad hoc review committee led by Harold Varmus of the RAC; see Science 270 (1995), 1287. A review of gene therapy has concluded that the technology has been oversold, there are few unambiguous examples in which patients have benefited from the technique (http://www.nih.gov/news/panelrep.html) Science 270 (1995), 1751; Nature 378 (1995), 655; Nature Medicine 1 (1995), 1137-9; NS (25 Nov 1995), 14-5.

A review is Hanania, E.G. et al. "Recent advances in the application of gene therapy to human disease", Amer.J. Med. 99 (1995), 537-52; also NEJM 333 (1995), 1204-7; PNAS 92 (1995), 9742-6. The need for safe and efficient gene transfer techniques to carry therapeutics is called for in GEN (15 Nov 1995),1, 26-7. Caution is also urged after the results of 5 patients in a liver trial, Grossman, M. et al. "A pilot study of ex vivo gene therapy for homozygous familial hypercholesterolaemia", Nature Medicine 1 (1995), 1148-54. The transfer of erythropoietin/interleukin-2 receptors to T cells is reported in Blood 86 (1995), 2281-7. The transfer of IL-2 secreting mouse fibroblasts containing tumor DNA induce immune responses that prolong the lives of mice, Cancer Gene Therapy 2 (1995), 183-90. The in situ expression of IL-4 as part of a tumor vaccine in cancer patients is reported in J. Immunology 17 (1995), 238-48. A gene therapy trial for Gaucher disease has begun in the USA with Targeted Genetics, Gene Therapy Newsletter 16 (1995), 5. On muscle-mediated gene therapy, NEJM 333 (1995), 1554-6. Gene therapy can also be used to regulate cell division, Nature Medicine 1 (1995), 1004-6.

In utero gene therapy in rat fetal epithelium has been obtained, Nature Medicine 1 (1995), 1201-3; which raises questions of fetal gene therapy, Nature Medicine 1 (1995), 864-6. Umbilical cord blood cells in ADA deficient babies are suggested as a further approach to that disease, Nature Medicine 1 (1995), 1017-24.

Brain tissue targeting is reported with herpes virus and adenovirus in rats in PNAS 92 (1995), 9829-90. Targeting of retroviruses by attached ligands has been achieved in breast cancer cells, PNAS 92 (1995), 9747-51; and into hepatocytes by baculovirus vectors, PNAS 92 (1995), 10099-103. In vitro skin culture is progressing, TIBTECH 13 (1995), 91-100. Manipulating immune response in allergic disease is discussed in TIBTECH 13 (1995), 186-90; and the biggest hurdle to gene therapy at the moment seems to be immunomodulation, Nature Medicine 1 (1995), 887-9. A live Leishmania vaccine (see vaccine section) has been made by genetic engineering, PNAS 92 (1995), 10267-71.

Due to falling numbers of cases to review the next quarterly meeting of the NIH RAC has been canceled, Nature 379 (1996), 668. They also have reduced the number of cases they review. The Japanese Ministry of health and Welfare guidelines on gene therapy in English are in WHO Int. Digest Health Legislation 46 (1995), 560-3. A report on the number of gene therapy protocols by country is in Nature Medicine 2 (1996), 136; with the numbers, USA 136; France 16; UK 13; Netherlands 7; Italy 7; Germany 5; China 3; Japan, Switzerland, Sweden and Austria 1 each.

On somatic gene therapy, BMJ 312 (1996), 323-4; Nature Medicine 2 (1996), 7-8, 144-7; NEJM 334 (1996), 332-3; Lancet 346 (1995), 1617. A review on the delivery of molecular medicine to solid tumours is in Science 271 (1996), 1079-1080. A method to modify human alleles by homologous recombination with targeting success in chicken ovalbumin locus of >90% and into the human beta-globin locus of 10-15% is Dieken, ES et al. "Efficient modification of human chromosomal alleles using recombination-proficient chicken/human microcell hybrids", Nature Genetics 12 (1996), 174-82. A review of research on engineering tissue grafts is Nature Medicine 2 (1996), 32-4; and on in utero stem cell transplants for treating inherited blood disorders, Nature Medicine 2 (1996), 161-2.

The negative results of a gene therapy trial for AIDS are in Riddell, SR et al "T cell mediated rejection of gene-modified HIV-specific cytotoxic T lymphocytes in HIV-infected patients", Nature Medicine 2 (1996), 216-23, 165-7; Lancet 347 (1996), 314. 5 of the 6 patients rejected the modified cells, so methods to prevent this will be needed for therapy. On antisense therapy, NEJM 334 (1996), 316-8.

Sweden will have a gene therapy research center next to Huddinge University Hospital, EBN 215 (1996), 4. Russia has approved research grants for gene therapy, Nature 379 (1996), 384.

At the beginning of March New Zealand entered the list of countries in which gene therapy has been performed, with the arrival of two American babies with Canavan disease and the New Zealand Professor working at Yale University, Science 271 (1996), 1489-90; 272 (1996), 467. It was the first trial to attack a disease of the nervous system, and used a new vector system. It is ethically interesting for the regulation of international gene therapy, and was only permitted after the review of the first decision of the Specially set-up Health Research Council Ethics Committee. The ethics of gene therapy is discussed in JAMA 275 (1996), 644-5; Kaura DR. "Drawing the line on genetic intervention in humans", CMAJ 154 (1996), 927-929.

From 25-27 March there was the Luneburg Symposium on Interdisciplinary Approaches to Gene Therapy, held at the University of Luneburg, Germany. The proceedings of the symposium will be published, and announced when they are. There were sessions on biological basics, clinical trials, biosafety, legal aspects, medical-economic aspects and ethical aspects, as well as social events. There was discussion of ethical issues throughout the meeting, and also a cafe Reflex set up which asked participants questions on the ethical aspects of gene therapy throughout the meeting. A number of international speakers and participants came, and it was held in English. Abstracts may be available earlier.

Parts of the report of H. Varmus on NIH investment in research on gene therapy is in BME 116 (1996), 10-11; as noted earlier the text is available on Internet . On gene therapy in German industry, GEN (15 March 1996), 3, 6; Biotechnology 13 (1995), 1031. On molecular medicine, Lancet 347 (1996), 555.

A review is Pergament, E. & Fiddler, M. "Prenatal gene therapy: Prospects and issues", Prenatal Diagnosis 15 (1995), 1303-11. Gene therapy trials against oral cancer are discussed in Nature Biotechnology 14 (1996), 243. 100-1000 times efficiency of gene transfer by Adeno-associated virus of hematopoietic stem cells was reported at a meeting in February, Nature Biotechnology 14 (1996), 269. A new vectors for gene transfer called virosome is reported in Hodgson, CP. & Solaiman, F. "Virosomes: cationic liposomes enhance retroviral transduction", Nature Biotechnology 14 (1996), 339-42. Cell-targeting is reported in Nature Medicine 2 (1996), 267-9, 276-7, 299-303; and tissue targeting in vivo in mice in Nature 380 (1996), 364-6. A review of liver gene therapy trials is Nature Genetics 12 (1996), 232-3, which follows a successful mouse model, Overturf, K. et al. "Hepatocytes corrected by gene therapy are selected in vivo in a murine model of hereditary tyrosinaemia type 1", Nature Genetics 12 (1996), 266-73. Skeletal muscle therapy is reported in rats in Nature Medicine 2 (1996), 418-23; vascular therapy in Lancet 347 (1996), 752; neuronal therapy in NS (9 March 1996), 17; and a review of CF gene therapy trials is TIG 12 (1996), 81-4. On HIV as a vector, Science 272 (1996), 195; and on lentiviral vectors into non-dividing cells, Science 272 (1996), 263-7. Gene therapy may be useful for radiotherapy protection, Lancet 347 (1996), 632. In general see Biotechnology 13 (1995), 1050-2; Lancet 347 (1996), 820.

The director of the NIH has recommended closing the RAC and leaving this work of review to the FDA and institutional committees, Science 272 (1996), 1569; NS (8 June 1996), 10; Nature 381 (1996), 635. Some are happy with this, Human Gene Therapy 6 (1995), 1361-2; while others worry about the lack of public oversight, Human Gene Therapy 7 (1996), 795-7. The loss of the RAC will have broader ramifications, those countries setting up review procedures have often modeled them on the public RAC and this has given reassurance to the public, as well as ensuring ethical improvements in the trials - the loss of the RAC will be an excuse for other countries not to have public review! There are other issues that the RAC should look at, such as fetal and germ-line gene therapy.

A paper looking at the germ-line issue is Juengst, ET. ""Prevention" and the goals of genetic medicine", Human Gene Therapy 6 (1995), 1595-1605. Papers on the topic of playing God include Peters, T. ""Playing God" and germline intervention", J.Med.&Phil. 20 (1995), 365-86.

The challenges to the broad gene therapy patent are discussed in Nature Biotechnology 14 (1996), 426. A review on safety is Smith, KT et al. "Gene delivery systems for use in gene therapy: an overview of quality assurance and safety issues", Gene Therapy 3 (1996), 190-200; see also Human Gene Therapy 6 (1995), 551-2. On the New Zealand Canavan gene therapy protocol, Science 272 (1996), 1085. A description from the UK Dept. of Health on the writing of information leaflets for patients is in Human Gene Therapy 7 (1996), 751-4.

Delivery efficiency has been increased ten-fold in a process called directed motion in which the genes are moved towards Cells, or a flow-through technique, GEN (1 May 1996), 33, 40; Human Gene Therapy (10 April, 1996). A review of Rgene Therapeutics gene therapy trials for ovarian and breast cancer is GEN (15 April 1996), 10-1. CNTF is being used in attempts to treat ALS patients, Nature Medicine 2 (1996), 696-9. Retinal degeneration may be treated by gene therapy, following a successful mouse study, Nature Medicine 2 (1996), 649-54. On antisense techniques, Nature Medicine 2 (1996), 634-5; BioEssays 17 (1995), 1055-63; PNAS 93 (1996), 3161-3; and using baculoviruses, PNAS 93 (1996), 2348-52.

Treatment of hypercholesterolemia in a mouse model using adenovirus and the VLDL receptor gene is reported in Nature Genetics 13 (1996), 54-62. On adenoviruses, NEJM 334 (1996), 1185-7; Nature Medicine 2 (1996), 714-6; Current Opinion in Biotechnology 6 (1995), 590-5; PNAS 93 (1996), 3056-61, 4513-8. There are some concerns that adenovirus vectors may damage the brain, NS (11 May 1996), 6. The use of ribozymes to correct gene products has been achieved, Nature Medicine 2 (1996), 643+; NS (15 June 1996), 16. Genetic engineering may be used indirectly to treat disease on competitive microorganisms of pathogens, Nature Biotechnology 14 (1996), 444-6. Reviews on use for cancer, Gene Therapy 3 (1996), 95-6, 97-102; inflammatory diseases, Gene Therapy 3 (1996), 187-9; and vascular diseases, Science 272 (1996), 689-93. On an unsuccessful HIV vaccine by gene therapy, PNAS 93 (1996), 3972-7.

Schering has joined the list of large companies getting links in gene therapy, EBN 223 (1996), 2; Nature Biotechnology 14 (1996), 570. There are a few journals focused on gene therapy, a recent addition is a weekly called Gene Therapy Weekly, which at US$1,195 a year is not one I subscribe too!

A case of what is called natural gene therapy, in which a patient born with an autosomal recessive immunodeficiency has been found to contain a subset of lymphocytes which have reverted back to the normal protein, Hirschhorn, R. et al. "Spontaneous in vivo reversion to normal of an inherited mutation in a patient with adenosine deaminase deficiency", Nature Genetics 13 (1996), 290-5, 255-6; NS (20 July 1996), 16.

Some reporting on the ethical review of New Zealand's first case of gene therapy is in Lancet 347 (1996), 1759; see EJAIB (May 1996). The US Congress has had concerns about the plan to close the RAC, Science 273 (1996), 21. India has announced the first research project on gene therapy, which will work on a suicide gene therapy against oral cancer, Nature 382 (1996), 201. On social and ethical issues a roundtable discussion is Hillman, AL. et al. "Gene therapy: socioeconomic and ethical issues. A Roundtable discussion", Human Gene Therapy 7 (1996), 1139-44. Another roundtable is in Leukemia 9 Suppl 1 (1995), S7-8.

A paper in response to a paper proposing mitochondrial germ-line therapy is Baccheta, MD. & Richter, G. "Dimensions and classification of genetic interventions in the human genome", CQHE 5 (1996), 450-7. They propose that in addition to considering tissue type (somatic/germ-line) and purpose (therapy/enhancement) the genome type (nuclear/mitochondrial) is also important in ethical analysis. To me it seems that genes are genes no matter where they are located, and we could add extragenome elements to effects gene therapy. Does it make a difference to ethical analysis? An older paper on germ-line is Torres, JM. "The importance of microevolutionary tenets in the debate on germ-line human gene therapy", Luolus Vitalis Vol II (No.3, (1994), 136-49. On the fast speed of evolution of the mitochondrial genome, AJHG 59 (1996), 501-9.

Another broad patent for gene therapy has been issued, this one for use of locus control regions (LCR) by Therexsys Ltd. (UK). LCRs are naturally occurring tissue-specific regulatory systems that ensure that the gene is expressed only in target tissues; EBN 226 (1996), 2. On suicidal vectors for improving safety, NS (10 August 1996), 20.

Success has been reported for the first trials in lung cancer, in which a normal copy of p53 was given and in 3 or 9 patients the tumours shrunk and in 3 they stopped growing, NS (31 August 1996), 14. New bone formation in rats was stimulated by gene transfer, Fang, J. et al. "Stimulation of new bone formation by direct transfer of osteogenic plasmid genes", PNAS 93 (1996), 5753-8; NS (22 June 1996), 14. On retinal engineering, PNAS 93 (1996), 6269-74. More on technical issues and new gene therapy research is in GEN (15 June 1996), 1, 3, 13, 15, 23, 38; Seminars in Oncology 23 (Feb. 1996); Lancet 348 (1996), 323, 370-4; Nature Medicine 2 (1996), 876-82; NEJM 335 (1996), 337-9; Science 273 (1996), 183; PNAS 93 (1996), 5731-6. The use of encapsulated genetically modified bacteria in rats is reported in Nature Medicine 2 (1996), 883-7.

A discussion of comments made by AV. Campbell about the clinical trial of gene therapy by Dr M. During in New Zealand is in Otago Bioethics Report 5 (July 1996), 5-6. However, the Auckland ethics committee has confirmed that its ethical approval for the phase 1 trial on Canavan's disease was appropriate and a letter by the scientist, MJ During is in Lancet 348 (1996), 618. On the debate on the scraping of the RAC, Nature 382 (1996), 191, 197.

Philosophical papers on the duty to future generations include Boonin-Vail, D. "Don't stop thinking about tomorrow: Two paradoxes about duties to future generations", Philosophy & Public Affairs 25 (1996), 267-^307; Parfit, D., "Acts and outcomes: A reply to Boonin-Vail", Philosophy & Public Affairs 25 (1996), 308-17; Shoemaker, DW. "Theoretical persons and practical agents", Philosophy & Public Affairs 25 (1996), 318-32.

On investment in gene therapy, Nature Biotechnology 14 (1996), 1216. Boehringer-Mannheim is believed to be making a large financial deal with the University of California San Diego, Science 273 (1996), 1647.

On the use of electroporation in clinics as well as laboratories, a review is GEN (15 Sept. 1996), 14-5. The use of HIV is being considered for gene therapy, Nature Biotechnology 14 (1996), 943. Actin-resistant Dnase I has been engineered for treatment of cystic fibrosis, PNAS 93 (1996), 8225-9. DNA immunization using dendritic cells is possible, Nature Medicine 2 (1996), 1122-8; and antitumour immunity using both chemokine and cytokine gene transfer is more efficient, Nature Medicine 2 (1996), 1090-5. There is some positive results from p53 gene insertion in lung cancer gene therapy, Lancet 348 (1996), 671.

A switch to allow patients to turn on or off inserted genes is being constructed, Nature Medicine 2 (1996), 1028. To monitor the presence of introduced genes and the distribution of the encoded proteins in host tissues after gene transfer, a research team combined fluorescence in situ hybridization (FISH) and immunohistochemistry in two separate gene therapy paradigms; Gussoni, E. et al. "A method to codetect introduced genes and their products in gene therapy protocols", Nature Biotechnology 14 (1996), 1012-6. The combined FISH and immunohistochemistry assay offers greater sensitivity and more information than currently used polymerase chain reaction and protein detection methods. On targeting in general, Nature Genetics 14 (1996), 121-3; PNAS 93 (1996), 8804-8; NS (4 Sept. 1996), 19. Adenoviruses are becoming safer, more effective, and specific, Nature Biotechnology 14 (1996), 948-50; and on retroviruses, J.Theo.Biol. 182 (1996), 1-20. On cell surface markers for assessing gene transfer, Nature Med. 2 (1996), 1154-6.

On the ethics of gene therapy, Law and the Human Genome Review 4 (Jan-June 1996), 125-40. A criticism of exagerated claims for gene therapy is GEN (15 Oct 1996), 4, 30.

The promise of adeno-associated virus vectors is discussed in Nature Biotechnology 14 (1996), 1725-7. Wickham, TJ et al. "Adenovirus targeted to heparan-containing receptors increases its gene delivery efficiency to multiple cell types", Nature Biotechnology 14 (1996), 1570-3; Douglas JT. et al. "Targeted gene delivery by tropism-modified adenoviral vectors", Nature Biotechnology 14 (1996), 1574-8, 1538. When complexed with an adenoviral vector carrying the gene for herpes simplex virus thymidine kinase, the Fab-folate conjugate mediated the specific killing of cells that overexpress the folate receptor. A review of the problems of adenovirus vectors is Wood, MJA. et al. "Immune responses to adenovirus vectors in the nervous system", TINS 19 (1996), 497-501. On retrovirus transfer, PNAS 93 (1996), 11871-6; and use in transfer of p53, Nature Medicine 2 (1996), 1163.

DNA vaccination is reviewed in Lancet 348 (1996), 1232. Arterial gene therapy may be possible, Lancet 348 (1996), 1380-2; as may skin tissue targeting, Nature Medicine 2 (1996), 1263-7. A review of extrachromosomal replicating gene vectors for gene therapy is TIG 12 (1996), 463-6.

The US NIH RAC has backed the reduction of its size from 25 to 15 members, Nature 384 (1996), 506; NatBio 15 (1997), 11. The new smaller RAC will still have its members appointed by the Secretary of Health and Human Services. Under the proposal, at least eight of them will be knowledgeable in the fields of molecular genetics, molecular biology, recombinant DNA research or other related fields. At least four others will be persons knowledgeable in applicable law, standards of professional conduct and practice, public attitudes, the environment, public health, occupational health or related fields, Geneletter (January 1997). The responsibilities will be: Identifying novel human gene transfer experiments deserving of public discussion by the full RAC and transmitting comments/recommendations about specific gene transfer experiments to the NIH director. Identifying novel ethical issues relevant to specific human applications of gene transfer and recommending appropriate modifications to the Points to Consider that will provide guidance in the preparation of relevant informed consent documents. Identifying novel scientific and safety issues relevant to specific human applications of gene transfer and recommending appropriate modifications to the Points to Consider that will provide guidance in the design and submission of human gene transfer clinical trials. Publicly reviewing human gene transfer clinical trial data captured by NIH/ORDA in accordance with the annual data reporting requirements. Identifying broad scientific and ethical/social issues relevant to gene therapy research as potential Gene Therapy Policy Conference topics.

On ethics, Dickens BM. "Legal and ethical challenges in gene therapy", Transfusion Science 17 (1996), 191-196.

On adenovirus dodecahedron, a new vector for human gene transfer, NatBio 15 (1997), 52-6, 17; and use of adenovirus for rat testis transfer in vivo Biology of Reproduction 56 (1997), 495-500. On VP22 vectors, NS (15 Feb, 1997), 25; and HIV vectors, PNAS 93 (1996), 14070-5. If Alzheimer's is linked to herpes it could halt use of herpes in gene therapy, NS (1 Feb, 1997), 10. Also on gene therapy, NatBio 15 (1997), 109, 118; PNAS 94 (1997), 79-84; 219-224; Liu, Y. et al. "Factors influencing the efficiency of cationic liposome-mediated intravenous gene delivery", NatBio 15 (1997), 167-73. Dopaminergic neurons can be protected from degeneration by GDNF gene therapy, Science 275 (1997), 838-41. A review of commercial development of vectors in gene therapy is GEN (1 Feb 1997), 8, 34. French studies by Transgene have found that gene therapy with Il-2 prolonged the lives of cats and dogs with spontaneous tumours, EBN 238 (1997), 3-4. p53 may be useful for treatment of bladder cancer, Nature 385 (1997), 123-5. Prolonged expression in skeletal muscle has been obtained, PNAS 93 (1996), 14082-7. On targeting to blood vessels, Science 275 (1997), 482-4, 547-50.

On business are involved in gene therapy NatBio 15 (1997), 12, 214; Nature 385 (1997), 108.

A downsized, reconstituted version of the US National Institutes of Health Recombinant DNA Advisory Committee (NIHRAC) agreed in March that gene therapy researchers may begin studying recombinant vectors in normal, healthy volunteers, Nature Biotechnology 15 (1997), 314; Science 275 (1997), 1561. Committee members also are calling for the first special conferences under NIHRAC's new regime, recommending that the use of normal volunteers in research and also proposals to test gene transfer as a means for human "enhancement" be scrutinized from an ethical as well as a scientific standpoint.

On genetic identity and philosophical issues of persons, Elliot, R. "Genetic therapy, person-regarding reasons and the determination of identity", Bioethics 11 (1997), 151-60; with a reply by Persson, I, pp. 161-69. A letter saying gene therapy is not eugenics is Nature Genetics 15 (1997), 234.

Overexpression of BCL-2 is common in non-Hodgkin lymphoma and leads to resistance to programmed cell death (apoptosis) and promotes tumorigenesis. In patients with relapsing non-Hodgkin lymphoma, BCL-2 antisense therapy led to an improvement in symptoms, objective biochemical and radiological evidence of tumour response, and down-regulation of the BCL-2 protein in some patients. Webb, A et al. "BCL-2 antisense therapy in patients with non-Hodgkin lymphoma", Lancet 349 (1997), 1137-41.

A review is Buchsbaum, DJ et al. "Approaches to enhance cancer radiotherapy employing gene transfer methods", Gene Therapy 3 (1996), 1042-68; and on use of multidrug resistance genes, Lancet 349 (1997), 858. The introduction of signal transduction products to clinical testing for gene therapy is reviewed in GEN (15 March 1997), 1, 27. Cystic fibrosis mice have been cured genetically in the womb, Lancet 349 (1997), 619-20; NS (20 March 1997), 20; and mice with motor neuron disease have benefited from adenoviral transfer of NT-3 and CNTF genes, Nature Medicine 3 (1997), 380-1, 429-36; also dopaminergic neurons were protected from degeneration by gene therapy, Science 275 (1997), 836-41. Stable expression of genes in muscle has been achieved with purified adeno-associated virus in mice, Nature Medicine 3 (1997), 278-9, 299-312. Prospects for gene therapy of osteogenesis imperfecta are reviewed in JAMA 277 (1997), 746-50. Herpes virus may be used for gene transfer into neurons, Nature Medicine 3 (1997), 357-9. On retrovirus vectors, Gene Therapy 3 (1996), 1069-73.

Human artificial chromosomes are being stabilized by new techniques to make them long lasting, Nature Genetics 15 (1997), 345-55; Nature 386 (1997), 553-5; NS (5 April 1997), 19. Frozen cord blood has been used for gene therapy in Israeli-Italian collaboration, Lancet 349 (1997), 705. A new facility in Milan is a joint Italian / German project on gene therapy, GEN (1 April 1997), 17.

A downsized, reconstituted version of the US National Institutes of Health Recombinant DNA Advisory Committee (NIHRAC) agreed in March that gene therapy researchers may begin studying recombinant vectors in normal, healthy volunteers, Nature Biotechnology 15 (1997), 314; Science 275 (1997), 1561. Committee members also are calling for the first special conferences under NIHRAC's new regime, recommending that the use of normal volunteers in research and also proposals to test gene transfer as a means for human "enhancement" be scrutinized from an ethical as well as a scientific standpoint.

On genetic identity and philosophical issues of persons, Elliot, R. "Genetic therapy, person-regarding reasons and the determination of identity", Bioethics 11 (1997), 151-60; with a reply by Persson, I, pp. 161-69. A letter saying gene therapy is not eugenics is Nature Genetics 15 (1997), 234.

Overexpression of BCL-2 is common in non-Hodgkin lymphoma and leads to resistance to programmed cell death (apoptosis) and promotes tumorigenesis. In patients with relapsing non-Hodgkin lymphoma, BCL-2 antisense therapy led to an improvement in symptoms, objective biochemical and radiological evidence of tumour response, and down-regulation of the BCL-2 protein in some patients. Webb, A et al. "BCL-2 antisense therapy in patients with non-Hodgkin lymphoma", Lancet 349 (1997), 1137-41.

A review is Buchsbaum, DJ et al. "Approaches to enhance cancer radiotherapy employing gene transfer methods", Gene Therapy 3 (1996), 1042-68; and on use of multidrug resistance genes, Lancet 349 (1997), 858. The introduction of signal transduction products to clinical testing for gene therapy is reviewed in GEN (15 March 1997), 1, 27. Cystic fibrosis mice have been cured genetically in the womb, Lancet 349 (1997), 619-20; NS (20 March 1997), 20; and mice with motor neuron disease have benefited from adenoviral transfer of NT-3 and CNTF genes, Nature Medicine 3 (1997), 380-1, 429-36; also dopaminergic neurons were protected from degeneration by gene therapy, Science 275 (1997), 836-41. Stable expression of genes in muscle has been achieved with purified adeno-associated virus in mice, Nature Medicine 3 (1997), 278-9, 299-312. Prospects for gene therapy of osteogenesis imperfecta are reviewed in JAMA 277 (1997), 746-50. Herpes virus may be used for gene transfer into neurons, Nature Medicine 3 (1997), 357-9. On retrovirus vectors, Gene Therapy 3 (1996), 1069-73.

Human artificial chromosomes are being stabilized by new techniques to make them long lasting, Nature Genetics 15 (1997), 345-55; Nature 386 (1997), 553-5; NS (5 April 1997), 19. Frozen cord blood has been used for gene therapy in Israeli-Italian collaboration, Lancet 349 (1997), 705. A new facility in Milan is a joint Italian / German project on gene therapy, GEN (1 April 1997), 17.

A new book is Muller, S, Simon, JW., & Vesting, J. eds., Interdisciplinary Approaches to Gene Therapy. Legal, Ethical and Scientific Aspects (Springer-Verlag, Berlin, 1997; 292pp, ISBN 3-540-63056-2), which includes the papers from the 1996 conference held in Luneburg, Germany. It is divided into 3 sections, science, law and ethics, 27 papers including Macer, D. (1997) "Ethical assessment of gene therapy in Asia", pp. 213-236.

A book review of Walter, L. & Palmer, JG. The Ethics of Human Gene Therapy (NY: Oxford Univ. Press 1997, 209pp., US28, ISBN 0-19-505955-7) is NEJM 336 (1997), 1843-4. A debate on gene therapy is Holtug, N. "Altering humans - the case for and against human gene therapy", CQHE 6 (1997), 157-74. On germ-line gene therapy, Biomedical Ethics 2 (1, 1997).

In July the first trial in Japan by a pharmaceutical company had been approved for HIV, NatMed 3 (1997), 482; but it has been postponed because of fears of cancer from the vector; Yomiuri Shimbun (28 June 1997), 1. A report on the debut of gene therapy in Korea prior to government guidelines is Science 276 (1997), 1035; Nature 387 (1997), 6. India is supporting a gene therapy program, NatMed 3 (1997), 595-6.

A series of review papers are in SA (June 1997), 95-123. A review of recent gene therapy trials in clinics by 16 companies is GEN (15 June 1997), 14, 35, 38; and on cancer trials, Lancet 349 (1997), 1605; NatMed 3 (1997), 515-20, 606-8, 612-3, 639-45; Science 276 (1997), 1719-24; Molecular Endocrinology 11 (1997), 667-73. Retroviral vectors are being refined by companies, GEN (15 June 1997), 27, 40; as are antisense approaches, Science 276 (1997), 1192-3; Lancet 349 (1997), 1137-41. Research on angiogenesis is reviewed in GEN (1 May 1997), 6, 33; and cystic fibrosis, Lancet 349 (1997), 1249-50.

A call for openness in gene therapy regulation is Lancet 350 (1997), 79; also BioScience 47 (1997), 139. HIV vectors may challenges gene therapy oversight, NatBio 15 (1997), 832. A review of Walters, L. & Palmer, JG. The Ethics of Human Gene Therapy (NY: Oxford Univ. Press, 1996, ISBN 0-19-505955-7, US$28, 209pp., is JAMA 278 (1997), 252-3. On gene therapy commercialization, NatBio 15 (1997), 689, 815.

Organ specific gene therapy for prostrate cancer using an enhancer gene, PSA, has been developed, GEN 17(August 1997), 1, 15, 34. Millington-Ward, S. et al. "Strategies in vitro for gene therapies directed to dominant mutations", Human Molecular Genetics (1997), 1415-26. A review of metabolic engineering and human disease is NatBio 15 (1997), 525-8. Cannizzo, S., et al. "Augmentation of blood platelet levels by intratracheal administration of an adenovirus vector encoding human thrombopoietin cDNA", NatBio 15 (1997), 570-3. This strategy may be a useful approach to the nonparenteral administration of a variety of therapeutic recombinant proteins, such as those relevant to clotting, endocrine function, and bone-marrow function. Stable expression of factor IX in mice is reported in PNAS 94 (1997), 5804-9; NatGen 16 (1997), 270-6. It is possible that unexpectedly high homologous recombination results reported last year were an artifact, Science 277 (1997), 460-2. A call for gene therapy trials of ovarian cancer is in O&G 89 (1997), 145-55. In general on techniques, NatMed 3 (1997), 719-20. 765-70, 806; TIBTECH 15 (1997), 217-23.

The Health Council of the Netherlands has released an English report, Committee on Gene Therapy, 84pp, No 1997/12E, 4 June 1997 (ISBN 90-5549-165-9). It addition to setting out the system for ethical review of research, and the need to support research applications for patients, they also called for a report on germ-line gene therapy and fetal gene therapy. A paper on the limits is Torres, JM. "On the limits of enhancement in human gene transfer: Drawing the line", J.Med. Phil. 22 (1997), 43-53.

Three children suffering from Hurler's syndrome have started gene therapy to introduce the missing gene, alpha-L-iduronidase, NS (2 Aug. 1997), 16. On oligonucleotide therapeutics, NatMed 3 (1997), 834-5. A review is Verma, IM. & Somia, N. "Gene therapy - promises, problems and prospects", Nature 389 (1997), 239-42. DNA vaccination onto bare skin can elicit immune responses, Nature 389 (1997), 729-30; and a review is Chattergoon, M. et al. "Genetic immunization: a new era in vaccines and immune therapeutics", FASEB J. 11 (1997), 753-63. Sensitization to morphine induced by viral-mediated gene transfer, Science 277 (1997), 812+; and antisense targeting to block tumour growth is reported in NatMed 3 (1997), 887+. Methods to build new pores in cells are reviewed in SA (Sept. 1997), 62-7.

Commercial exchanges between biotech companies and pharmaceutical companies in gene therapy are reviewed in GEN (1 Oct. 1997), 4, 40. On the use of electroporation for gene or drug delivery, GEN (15 Sept. 1997), 19, 37. A gene therapist has been accused of research fraud in Germany, Nature 389 (1997), 105.

On ethics, Holtug, N. "Altering humans: The case for and against human gene therapy", Monash Bioethics Review 16 (October 1997), 14-31; Juengst, ET. "Can enhancement be distinguished from prevention in genetic medicine", J. Med. & Phil. 22 (1997), 125-42. When US National Institutes of Health (NIH; Bethesda, MD) director Harold Varmus downsized the NIH Recombinant DNA Advisory Committee (NIHRAC), he also promised to convene periodically conferences to review gene therapy-related issues. Participants at the first of those conferences, held in mid September, 1997, considered on what ethical and technical grounds clinical procedures based on gene transfer technology may be used to "enhance" individuals, NatBio 15 (1997), 1236. On the role of the FDA in regulation, NatMed 3 (1997), 1084-5. On the history of cosmetic surgery, Nature 390 (1997), 571-2; and limits to gene therapy, NS (25 Oct 1997), 20-1.

On nonviral strategies for gene therapy using lipid-based vectors by Megabios Comp., and plasmids by GeneMedicine, GEN 18 (Jan 1, 1998), 13, 28, 32. On the future of molecular medicine, GEN 17 (Dec 1997), 20, 38; AJHG 61 (1997),785-9, 790-4; NatMed 3 (1997), 1409-10; BMJ 315 (1997), 1289-92; Time (Jan 1998), 42-51; PNAS 94 (1997), 12744-6; Science 277 (1997), 1945; 278 (1997), 235. A non-retroviral RNA virus can persist in a DNA form, Nature 390 (1997), 298-301. On gene therapy techniques, NatMed 3 (1997), 1295-7; PNAS 94 (1997), 14547-52; and stem cells, JAMA 278 (1997), 1477-8.

IntroGene of the Netherlands has reported success in longterm expression of human beta-globin genes in rhesus monkeys, GEN 17 (15 Nov 1997), 31. Sustained expression of genes in the liver and muscle by lentiviral vectors is reported in NatGen 17 (1997), 314-8. Expression of truncated utrophin can help MD models, NatMed 3 (1997), 1216-21; tumour regression, NatMed 3 (1997), 1354-61, 1362-8; BMJ 315 (1997), 1604-7; PNAS 94 (1997), 13862-7; and on diabetes, NatMed 3 (1997), 1402-8. On vascular gene therapy results, Lancet 350 (1997), 1451.

A book review of Walters, L. & Palmer, JG., The Ethics of Human Gene Therapy (Oxford University Press, 1997, 209pp.) is in AJMG 75 (1998), 542-3. A discussion of gene therapy ethics is CQHE 7 (1998), 90-3. A book review of Haiken, E. Venus Envy. A History of Cosmetic Surgery (John Hopkins Univ. Press 1997) is in Lancet 351 (1998), 377. In general on gene therapy, NS (10 Jan. 1998), 44.

A survey of Russian attitudes to genetics is in Gudkov, L. et al. "Human genetic improvement: a comparison of Russian and British public perceptions", BME 134 (1998), 20-3. It suggests there is greater support for technological solutions than in the UK, and the survey found them more supportive of enhancement than in the UK (different to the survey in 1993 by Kaushik and Macer, in Bioethics for the People by the People, 1994). This may be due to the more conservative attitudes this survey found among residents of St. Petersburg and Moscow, as the 1993 survey focused on major cities.

On DNA vaccination, NatMed 4 (1998), 147-8. Several papers on delivery systems include: Arras, M. et al. "The delivery of angiogenic factors to the heart by microsphere therapy", NatBio 16 (1998), 159-62, 136, 172-6, 181-5; Kuo, PY. et al. "Topical antibody delivery systems produce sustained levels in mucosal tissue and blood", NatBio 16 (1998), 163-7. In vivo electrically mediated protein and gene transfer has been performed in mice, NatBio 16 (1998), 168-9; and on adenovirus transfer with decreased toxicity, NatGen 18 (1998), 180-3; PNAS 95 (1998), 1213-7; and in liver allografts, NatMed 4 (1998), 194-200; and vector issues, Lancet 351 (1998), 346. On reduction of triplet repeat disorders, NatGen 18 (1998), 111-7. On bacterial delivery of DNA, NatBio 16 (1998), 138; and bcl-2 antisense therapy, NatMed 4 (1998), 232-4; SCID therapy, NatMed 4 (1998), 19-20, 58-64; and antitumour therapy in mice, NatMed 4 (1998), 168-72; Science 279 (1998), 377-80. Protocols for using genes against chemotherapy side effects are being tried, Lancet 351 (1998), 116; and therapy against chronic myelogenous leukemia, Lancet 351 (1998), 40.

Germ-line gene therapy may receive support in the USA, after a panel discussion on the subject; Nature 392 (1998), 315, 317. The question is when there are alternatives and it is safe and effective. Some comments were critical, Nature 392 (1998), 645. A review of a report on genetic intervention in human subjects by the Catholic Bishops Committee in the UK is in JME 23 (1997), 385.

In vivo gene therapy without viruses has been performed in rats, Kren, BT. et al. "In vivo site-directed mutagenesis of the factor IX gene by chimeric RNA/DNA oligonucleotides", NatMed 4 (1998), 285-90, 274-5. A review of viral vectors is TIBTECH 16 (1998), 35-40; see also TIG 14 (1998), 136-7; Nature 392 (1998), 561. On methods to switch off cancer genes, NS (7 Feb. 1998), 36-9. Safety of a HIV-1 based vector is questioned in Lancet 351 (1998), 808.

On July 22, scientists from Hawaii said that they have made more than 50 clones and even cloned some of those clones (see also the Animal Genetic Engineering section, and ART), Nature 393 (22 July 1998). Mice were considered very difficult, but the work took a year. It means that cloning of humans will be technically possible very soon. The same issue of Nature includes papers showing Dolly was indeed a clone.

A report from a 10 panel lay persons discussion on gene therapy held associated with STS conferences in Osaka, Japan in March 1998 is Splice 4 (May/June 1998), 6-7. The question of whether designer genes for enhancement will be allowed is departed in TIBTECH 16 (1998), 281. A further report on the discussion of germline gene therapy at UCLA, that considered what technical obstacles need to be overcome before trying germline gene therapy experiments in humans, is in NatBio 16 (1998), 407; NatGen 19 (1998), 10-1. Some reproductive cells may have been modified by accident in some clinical trials, NS (14 March 1998), 7. A trial of gene therapy against kidney cancer at University of Tokyo has been approved by the MHW panel in Japan, and awaits the Ministry of Education committee to become the second gene therapy trial in Japan Japan Times (23 July 1998), 2.

Researchers fear a ban on lentivirus gene therapy, NatBio 16 (1998), 407. Fluorescent viral vectors are described in NatMed 4 (1998), 635-7. A review is Russell, DW. & Hirata, RK. "Human gene targeting by viral vectors", NatGen 18 (1998), 325-31. Targeting is improving, NS (11 April 1998), 7. Genetically altered placenta can maintain a fetus without transferring the genes or cells, which can deliver soluble factors to the fetus, NS (2 May 1998), 10; J. Clinical Investigation 101 (1998), 1565+. Other cases of fetal gene therapy are being reported, Human Gene Therapy (June 1998).

A general review is Sandhu, JS. et al. "Human gene therapy", Critical Reviews in Biotechnology 17 (1997), 307-26. A suicide based gene therapy has killed human osteosarcomas in nude mice, GenEng News 18 (15 April 1998), 1, 8, 36. Gene therapy also has had some success against breast and ovarian cancer, Lancet 351 (1998), 962; Science News 153 (11 April 1998), 239. A method for switching transgene expression in the brain using an adenoviral tetracycline-regulatable system is described in NatBio 16 (1998), 553-6. Intercellular delivery of functional p53 by the herpesvirus protein VP22 is discussed in NatBio 16 (1998), 440-3; and for liver disease, NatMed 4 (1998), 698-704. Persistent gene transfer of CFTR in maxillary sinus is reported in Lancet 351 (1998), 1702-3. On gene therapy for neurological disorders, NatMed 4 (1998), 632-3.

A successful research trial is Berglund, P. et al. "Enhancing immune responses using suicidal DNA vaccines", NatBio 16 (1998), 562-5. DNA vaccine efficacy can be greatly enhanced using plasmids designed to launch self-replicating viral RNA expression vectors. Two papers demonstrate that significantly smaller doses of alphavirus-based plasmid DNA vectors are necessary to achieve protection in mice than conventional DNA vectors, NatBio 16 (1998), 517. On the use of synthetic antisense oligonucleotides to selectively and specifically block target gene expression, NatBio 16 (1998), 496. Site directed immunogenesis is described in NatMed 4 (1998), 547-8. Gene therapy is being applied to treatment of HIV-1 infection, Lancet 351 (1998), 1709.

The implications of gene therapy for informed consent are discussed in JLME 26 (1998), 38-54. A review paper is Martin, PA & Thomas, SM. "The commercial development of gene therapy in Europe and the USA", Human Gene Therapy 9 (1998), 87-114. Reviews of gene therapy patents appear in various issues of Human Gene Therapy 9 (1998). On development in companies, EN (1 Sept. 1998), 42. Gene therapy still has a role in the developing world, Gene Therapy 5 (1998), 3-4. Naked DNA has been called poor man's gene therapy, but it may have some advantages, Gene Therapy 5 (1998), 573-4. A review of 4 years of progress in 4 children treated with ADA gene found that further improvements are needed before the gene itself is sufficient for immune function, NatMed 4 (1998), 775-80. On hematopoietic transplantation, NatMed 4 (1998), 896-7.

Ways to stop immune rejection of adenovirus in vectors are being developed, Human Gene Therapy 9 (1998), 454-6. A vector that has all viral coding sequences deleted resulted in enhanced safety and longer expression, PNAS 95 (1998), 7866-71. A review is Yanez, RJ. & Porter, ACG "Therapeutic gene targeting", Gene Therapy 5 (1998), 149-59. On cell-specific targeting with retroviral vectors, Human Gene Therapy 9 (1998), 767-70. New markers have been developed using flow cytometry and cell surface antigens, Gene Therapy 5 (1998), 429-30. On gene therapy progress for CF, Gene Therapy 5 (1998), 291-2; and for angiogenesis, PNAS 95 (1998), 8795-800, 8829-34, 9064-5. On genetically modified tumour vaccines, Gene Therapy 5 (1998), 147-8. Gene transfer to the mouse oviduct is reported in vivo using liposomes in F&S 70 (1998), 366-8. Vascular targeting for cancer therapy is discussed in NEJM 339 (1998), 472-3.

A book review on the idea of genethics is Bioethics 12 (1998), 334-5. French Anderson has asked the NIH RAC to consider the conditions needed for planned in utero gene therapy trials (probably two years later), with the possibility of possible germ-line modification as a result, GenEthics News 25 (Aug. 1998), 1-2, 6-7; Nature 395 (1998), 8, 309, 420; NatBio16 (1998), 1002-1003; Science 282 (1998), 27. Fetuses that are going to be aborted may be used for gene therapy trials, NS (10 Oct. 1998), 3, 5.The question of humanness is discussed in Campbell, A. et al. "Describing our "humaneness": Can genetic science alter what it means to be "human"?", Science & Engineering Ethics 4 (1998), 413-26. A discussion of the potential to make superhumans is NS (3 Oct. 1998), 24-9.

Two new books on advancing techniques in gene therapy are: Scanlon, Kevin J. Therapeutic Applications of Ribozymes (Methods in Molecular Medicine, Humana Press, Totowa, NJ. 1998, 462pp.); (see review in NatMed 4 (1998), 1198-9); Scanlon, KJ. & Kashani-Sabet, M. Ribozymes in the Gene Therapy of Cancer (Medical Intelligence Unit 4, R.G. Landes Company, Austin, Texas 1998, 236). Ribozymes may be able to selectively inhibit the expression of RNA so have use in medical therapy. Oral delivery of adenoviruses has been effective for gene therapy in rats, NatMed 4 (1998), 1121-2, 1131-5. On stem cell marking, NatMed 4 (1998), 1118-9, 1201-5. Cancer therapy is a subject of many trials, NatMed 4 (1998), 1012-3. On antisense therapy, SA (Nov. 198), 4, 50; JAMA 280 (1998), 871.

Introgen has created a new firm, Gendux to commercialize gene therapy, GEN (15 Oct. 1998), 6, 34, 45. A gene therapy trial involving transfer of cytochrome P450 expressing cells to pancreas against cancer has commenced in Germany, GEN (1 Oct. 1998), 1, 26, 42.

A book review of Parens, E., ed., Enhancing Human Traits: Ethical and Social Implications (Georgetown University Press, 1998, 251pp.) is in Nature 397 (1999), 222-3. On enhancement, NS (14 Nov. 1998), 58. A conference on in utero gene therapy has called for more discussion of ethical issues, Nature 397 (1999), 94. The idea of undoing aging has large ethical questions, NS (5 Dec. 1998), 49. On ethical issues, Richter, G. & Baccheta, MD. "Interventions in the human genome: Some moral and ethical considerations", J. Med. & Phil. 23 (1998), 303-17. The Campaign Against Human Genetic Engineering (CAHGE) is against such experiments on germ-line gene therapy. The Campaign Against Human Genetic Engineering (Email: cahge@globalnet.co.uk; <http://www.users.globalnet.co.uk/~cahge>) set up a website to allow opponents of human genetic engineering to send Email to US decision makers. They called on people to Email the US Recombinant DNA Advisory Committee (RAC).

Japan's second gene therapy clinical trial began on 5 October, 1998 at Tokyo University, however the vector development group DNAVEC has not produced local vectors in Japan, NatMed 4 (1998), 1213. European gene therapy trials are reported from a Israeli meeting, Lancet 352 (1998), 1834. The first antisense drug has been approved by the FDA called Fomivirsen, marketed by Ciba Vision, SA (Nov. 1998), 49-50.

Expression of full-length utropin gene prevents muscular dystrophy in mdx mice, NatMed 4 (1998), 1441-4. IGF-1 can also aid muscle growth, NS (2 Jan. 1999), 6. Potential gene therapy on X-linked adrenoleukodystrophy is discussed in NatMed 4 (1998), 1261-8; and on osteoarticular disease, Immunology Today 19 (1998), 387-91. Cancer gene therapy for dogs is one model, NatBio 17 (1999), 8. Thymic lymphoproliferative disease resulted after CD40 ligand correction in mice, NatMed 4 (1998), 1253-60. Hepatic gene therapy is discussed in Human Gene Therapy 9 (1998), 295-304; Clinical Genetics 54 (1998), 380-4. On expanding the types of vectors for gene therapy, GEN (Jan 1999), 3, 28. HIV-based vectors are also being used, Science 282 (1998), 1438; reoviruses, Science 282 (1998), 1332-4; mycoplasmas, NatBio 17 (1999), 4; and on adenoviral vectors, PNAS 95 (1998), 13159-64; and RNA virus vectors, PNAS 95 (1998), 12750-2; NatBio 17 (1999), 9. In general on viruses to attack cancer, Science 282 (1998), 1244-6.

Book review - by Darryl Macer

Parens, Erik., ed., Enhancing Human Traits: Ethical and Social Implications (Georgetown University Press, 1998, 288pp., Hard cover, IS$50, ISBN 0-87840-703-0).

This book is one of the Hastings Center Studies in Ethics, although it is published by Georgetown University Press. It includes 13 chapters with topics examining enhancement today, and in the future. It is quite timely given the debates on enhancement gene therapy, and the questions on the limits to improving the human body.

The general approach is philosophical asking when enhancement is better and when it is not, and the topic is not restricted to gene therapy. The authors include: Erik Parens, Eric Juensgt, Dan Brock, David Frankford, Anita Silvers, Kathy Davis, Caroil Freedman, Ronald Cole-Turner, Margaret Olivia Little, Carl Elliot, Susan Bordo, Gerald McKinny and Mary Einkler. There are certainly no easy boundaries between therapy and enhancement, but the book contributes to the debate over whether we should draw boundaries and in which cases. The price is rather high, so we can hope a paperback version is released.

On ethical issues of gene therapy, Human Genome News 10 (Feb 1999), 15-7. Human gene therapy is discussed in Italian in Il Mondo (19 Feb. 1999), 64-6. A paper against germ-line gene therapy is GeneWatch 11 (Jan 1999), 1, 3-4; and also CQHE 8 (1999), 88-96. For germ-line therapy, JLME 26 (1998), 211-20; NatMed 5 (1999), 245. A book review on protecting future generations is Bioethics 13 (1999), 160-73. A debate on in utero gene therapy is NatMed 5 (1999), 255-7; Nature 397 (1999), 383. On genetic enhancement, Science 283 (1999), 2023-4. The US is allowing fertile people to use gene therapy, even given the chance some germ cells could be modified by accident, NS (20 March 1999), 22.

Japan has approved several recent trials for gene therapy but still only a total of 3 with 3 patients have began, NatBio 17 (1999), 212; NatMed 5 (1999), 2.

A review of gene targeting is TIG 15 (1999), 88-90; Nature 398 (1999), 387; and a book review of a Textbook of Gene Therapy is NatMed 5 (1999), 371. Dosing gene therapy for Parkinson's Disease is reported in Corti, O. et al. "A single adenovirus vector mediates doxycycline-controlled expression of tyrosine hydroxylase in brain grafts of human neural progenitors" , NatBio 17 (1999), 349-354; 318. Gene therapy on demand is discussed in Encell, LP. et al. "Improving enzymes for cancer gene therapy" , NatBio 17 (1999), 143-147; 120. Spliceosome-mediated RNA trans-splicing as a tool for gene therapy is reported in NatBio 17 (1999), 223, 246-52; cationic lipid-mediated CFTR gene transfer to lungs and nose of patients, Lancet 353 (1999), 947-54; and adenoviral gene transfer in vivo, PNAS 96 (1999), 355-60.

On vectors for gene therapy, PNAS 96 (1999), 324-6. HIV is being debated as a vector, NS (6 Feb. 1999), 5. Oral gene delivery is reported using chitosan-DNA nanoparticles in a mouse model of peanut allergy, NatMed 5 (1999), 380-1, 387-91. Neonatal gene transfer corrected a mouse model of lysosomal storage disease, PNAS 96 (1999), 2296-300. Rat experiments suggest some hope in gene therapy for reversing liver damage, NatMed 5 (1999), 226-30; NS (6 Feb. 1999), 16. The regulated delivery and expression of EPO in mice and rhesus monkeys is reported in Science 283 (1999), 88-91. On correction of hemophilia B in canine and murine models, NatMed 5 (1999), 56-9, 64-70, 21-2.

A paper against germ-line gene therapy is Billings, PR. et al. "Human germ-line gene modification: a dissent", Lancet 353 (1999), 1873-5.

Sustained correction of bleeding in hemophilia B mice has been reported, PNAS 96 (1999), 3906-10. Gene therapy vectors can take beta-endorphins into the spinal cord to relieve pain in animals, Lancet 353 (1999), 1595. New methods for gene therapy are reviewed in GEN 19 (1 June 1999), 8, 16, 42. Use of an aerosol gene therapy trial for cystic fibrosis in Stanford is commencing, BMJ 318 (1999), 1096. High pressure can insert antisense DNA into cells of blood vessels before they are implanted into patients, NS (6 May 1999), 6; and electrical pulse has been used for skeletal muscle, PNAS 96 (1999), 4262-7. New lipid vectors are reported in NS (22 May 1999), 25. An explanation for a block in retroviral-mediated gene transfer has been found, due to the need for a conformational change, PNAS 96 (1999), 4005-10. Hepatocyte gene therapy is reported in PNAS 96 (1999), 3981-6.

On the ethics of germ-line gene therapy, CQHE 8 (1999), 369-74. A book review of Walters, L. & Palmer, JG. The Ethics of Gene Therapy (Oxford University Press 1997, 209pp.) is in HCR 29 (May-June 1999), 43. Enhancement is discussed in Holtug, N. "Does justice require genetic enhancements?", JME 25 (1999), 137-43. The RAC is still involved in gene therapy regulation and policy although not legally required, Science 284 (1999), 2066; Nature 400 (1999), 4.

Results of gene therapy with p53 to lung cancer found promising results in half the patients, Science News 15 (1999), 310; J. Natl. Cancer Institute (5 May 1999). The use of nitric oxide gene therapy is discussed in GEN 19 (15 June 1999), 23, 43. Green fluorescent protein is one marker of transfer, NatMed 5 (1998), 843-7. Cancer therapy using a self-replicating RNA vaccine is reported in NatMed 5 (1998), 823-7. Induction of the p16 senescence gene is a new therapeutic strategy for rheumatoid arthritis, NatMed 5 (1998), 731-2, 760-7. Prolonged therapy using direct plasmid gene delivery can work, NatMed 5 (1998), 707-10, 753-9. Murine erythropoietic protoporphyria photosensitivity can be cured by preselective gene therapy, NatMed 5 (1998), 768-73. The effect of adenovirus-mediated gene transfer for organ transplants is reported in Transplantation Proceedings 31 (1999), 1944-5. However, adenoviral vectors can be unstable in transport, NatMed 5 (1998), 955-7. On lentiviral vectors, Science 285 (1999), 674-6. Gene therapy and tissue engineering can speed up bone regeneration, NatMed 5 (1998), 733-4. Slow release DNA from a matrix may work, NatBio 17 (1999), 551+; NS (5 June 1999), 7. A general book review is NatMed 5 (1998), 728-9; Science 285 (1999), 1215-6; and for rare diseases, NatGen 22 (1999), 313-4. On repair of the genomes mistakes, Science 285 (1999), 316-9; NS (21 August 1999), 42-45. A campaign against human genetic engineering has been set up in the UK, Splice 5 (Sept. 1999), 7. A review of Agius, E. & Busuttil, S., eds, Germ-Line Intervention and our Responsibilities to Future Generations (Kluwer Academic Pub. 1998, 174pp., US$120) is, and killing and letting die in Bioethics 13 (1999), 433-6. The question of genetic engineering of humans is discussed in NS (23 Oct. 1999), 3-5. The Pontifical Academy for Life has maintained its view that it is wrong to modify the human germ-line, Japan Times (29 Nov. 1999), 10. A review is Zanjani, ED. & Anderson, WF. "Prospects for in utero human gene therapy", Science 285 (1999), 2084-7; pp. 2071-2.

There are concerns that germ-line transmission may occur in somatic cell trials, following a rat experiment, NS (20 Nov. 1999), 7. Discussion of the gene therapy safety inquiry is Nature Biotechnology 18 (2000), 8. There may be tougher rules following a patient death, NS (18 Dec. 1999), 9; Science 286 (1999), 2244-5. Safety and privacy are discussed in GEN 20 (1 Jan. 2000), 1, 11, 45. On the future enhancement of humans, Newsweek (27 Dec. 1999), 61-3C.

For SCID and hemophilia B there are encouraging signs that gene therapy may be working, Lancet 354 (1999), 2057. The hair follicle as a gene therapy target is discussed in Nature Biotechnology 18 (2000), 20-1. The use of telomerized cells for tissue engineering is discussed in Nature Biotechnology 18 (2000), 22-3. Gene therapy is being tested on Alzheimer's patients, NS (25 Dec. 1999), 4.

Synthetic DNA delivery systems are discussed in Nature Biotechnology 18 (2000), 33-7. Recent trials include: Thomas, M. et al. "Formation of functional tissue from transplanted adrenocortical cells expressing telomerase reverse transcriptase", Nature Biotechnology 18 (2000), 39-42; Alexeev, V. et al. "Localized in vivo genotypic and phenotypic correction of the albino mutation in skin by RNA-DNA oligonucleotide", Nature Biotechnology 18 (2000), 43-7. Genetic enhancement of cancer therapy is described in Lancet 354 (1999), 1999-2000.

Discussion of the death from a trial in Pennslyvania is SA (Feb. 2000), 36-7; Science 287 (2000), 591-2; Lancet 355 (2000), 329, 384; NatMed. 6 (2000), 1, 6, 118. Gene therapy should welcome public scrutiny, NatBio 18 (2000), 123-4, 143-4, 254-5. The FDA has halted all gene therapy trials at the University of Pennsylvania because it breached regulations, Science 287 (2000), 565-6; BMJ 320 (2000), 336; Nature 403 (2000), 354. The NIH has also been criticized, Nature 403 (2000), 237, 583-4, 703. The ethics of in utero gene therapy are discussed in Nature Genetics 24 (2000), 107.

However there are two positive reports from gene therapy trials that may show some efficacy, one on SCID and one on hemophilia, JAMA 283 (2000), 589-90. See: Tung, TTT. Et al. "In vivo bypass of hemophilia A coagulation defect by Factor XIIa implant", NatBio 18 (2000), 289-95, 264. In vivo visualization of gene expression using magnetic resonance imaging is reported in NatBio 18 (2000), 321-5. Use of lentiviruses is discussed in Nature Genetics 24 (2000), 8-9; NS (15 Jan. 2000), 8. Adeoviruses can be used to transfer genes to the peripheral nervous system, PNAS 97 (2000), 442-7. The future of gene therapy is discussed in Lancet 354 (1999), 2000 Supplement 22. Sickle cell disease has been corrected in transgenic mice studies, NatMed. 6 (2000), 139-40, 177-82. A review on cardiovascular disease trials is Lancet 355 (2000), 213-22. On electrotherapy, PNAS 97 (2000), 354-9.
;Following the review of gene therapy since the disclosure of deaths from the trials, the NIH and FDA will give greater scrutiny to adenoviral vector trials, HCR 30 (Jan. 2000), 6; GEN 20 (1 April 2000), 1, 28, 45; GeneWatch 13 (Feb. 2000), 1, 6-9; Bioethics Examiner 4 (Spring 2000), 1, 6; Nature 404 (2000), 5; Science 287 (2000), 1751: NS (18 March 2000), 5; Friedmann, T. "Principles for human gene therapy studies", Science 287 (2000), 2163-5; Nature Genetics 24 (2000), 201-2; NatBio 18 (2000), 123, 143-4, 377; Lancet 355 (2000), 560. The number of adverse effects reported from adenovirus trials increased a further 50%, to 970 adverse effects in 70 trials over 7 years, Nature 404 (2000), 119. The RAC in March 2000 meeting said that more animal data will be needed for future adenoviral trials. The FDA shut down gene therapy trials at the University of Pennsylvania after many lapses in their monitoring of trials, Nature 403 (2000), 820; Lancet 355 (2000), 997. Some other studies have also been put on hold, Lancet 355 (11 March 2000). The US government has been investigating also, NatMed. 6 (2000), 235. A report of HIV contamination of one gene therapy trial proved to be false, Lancet 355 (2000), 634, 733.

;A new book is Nordgren, A. ed., Gene Therapy and Ethics (Upsala 1999, ISBN 91-554-4640-X, 175pp.). It includes papers from a 1998 conference held in Uppsala, Sweden. A book review on genetic enhancement is in Bioethics 14 (2000), 93-5. A paper asking why we want to try genetic engineering of ourselves is Harris, J. "Intimations of immortality", Science 288 (2000), 59.

;The use of a DNA vaccine is reported in NS (25 March 2000), 9. Scientists at the Immune Response Corp. (USA) have synthesized a new gene for factor VIII that may be more suited for gene therapy of hemophilia, GEN 20 (1 March 2000), 6, 24, 56. The inhibition of experimental liver cirrhosis in mice by telomerase gene delivery is discussed in Science 287 (2000), 1253-8, 1258-62; Lancet 355 (2000), 630. VEGF gene transfer may be useful for ischemic peripheral neuropathy in rabbits, NatMed. 6 (2000), 405-13; NatBio 18 (2000), 368.

;The use of liposomes is reported in Domashenko, A. "Efficient delivery of transgenes to human hair follicle progenitor cells using topical lipoplex", NatBio 18 (2000), 420-3. The use of pressure to transfer DNA into cells is a new method, SA (March 2000), 34. Merck company has not agreed to extend a license to Baylor College to use a safe adenoviral vector in human clinical trials, Nature 403 (2000), 817. On use of suicide genes to kill cancer cells, NS (18 March 2000), 13. Gene therapy of experimental brain tumours in rats using neural progenitor cells is reported in NatMed. 6 (2000), 447+. Antisense therapeutics are reviewed in NatBio 18 (2000), 403-4. In general on gene therapy, Science & Medicine (Jan/Feb. 2000), 4-5. A series of 7 papers on genetic enhancement are in CQHE 9 (2000), 299-380. These include: McGee, G. "Ethical Issues in Enhancement: An Introduction", pp. 299-303; Daniels, N. "Normal Functioning and the Treatment-Enhancement Distinction", pp 309-322; Lachs, J. "Grand Dreams of Perfect People", pp 323-329; Goering, S. "Gene Therapies and the Pursuit of a Better Human", pp 330-341; Shickle, D. "Are "Genetic Enhancements" Really Enhancements?", pp 342-352; Miller, FG. "Cosmetic Surgery and the Internal Morality of Medicine", pp 353-364; Resnik, D. "The Moral Significance of the Therapy-Enhancement Distinction in Human Genetics", pp 365-377. The second part of a paper is Kirby, M. "Human freedom and the human genome" (Part II}", Law & Human Genome Review 11 (1999), 71-84. A report from the RAC is RAC, "Prenatal gene transfer: Scientific, medical and ethical issues", Human Gene Therapy 11 (2000), 1211-29. On the dangerous promise of gene therapy, BME 156 (2000), 13-7; JME 26 (2000), 89-94. On immortality, Science 288 (2000), 1345-7.

Lessons from the Gelsinger case are discussed in NS (20 Jan. 2000), 8; Science 290 (2000), 2049-50 On clinical use of gene therapy, JAMA 284 (2000), 2788; NS (23 Dec. 2000), 23. Focal modification of electrical conduction in the heart by gene transfer is reported in NatMed. 6 (2000), 1395-8. Prospects for diabetes treatment are also emerging as gut cells were engineered to produce insulin, Lancet 356 (2000), 1987; BMJ 321 (2000), 1488; Nature 408 (2000), 420-1, 483-8. Also on gene therapy, Lancet Perspectives 356 (2000), s8. BCL2 antisense therapy allowed chemosensitisation of malignant melanoma, Lancet 356 (2000), 1728. On gene thersapy for cancer, GEN (15 Nov. 2000), 1, 15, 58.

Techniques are improving, Hatada, S. et al. “Gene correction in hematopoietic progenitor cells by homologous recombination”, PNAS 97 (2000), 13807-11. Maternal germ-line transmission of mutant cDNAs from ES stem cell derived chimeric mice is reported in PNAS 97 (2000), 14461-6. Gene therapy might keep arteries open, Science News 158 (2000), 325; or as pacemakers, NS (9 Dec. 2000), 23. On Parkinbson's disease, NatMed<. 6 (2000), 1207-8. Receptors can be used to target gene vectors, Biotechnology & Bioengineering 70 (2000), 593-605. Artificial chromosomes are now being used in gene therapy, Science 290 (2000), 1308-9. On recombination, NatGen 26 (2000), 388-9.

The FDA has said that the public have a right to see the data on gene therapy and xenotransplantation, Nature 409 (2001), 442; Science 291 (2001), 572-3; Lancet 357 (2001), 292. Some have said that current FDA rules are not practical, NatBio 19 (2001), 5. A report on the problems that led to Jesse Gelsinger's death is NS (Jan. 2001), 8. On the future of human evolution, NS (13 Jan. 2001), 24-8; SA (March 2001), 42-7.

   The UK GTAC is continuing to allow SCID gene therapy trials similar to the one in France where leukemia is reported, but with closer monitoring, BME 182 (Oct. 2002), 5-6. The RAC in the USA said trials would also continue there, Science 298 (2002), 2113-4; NatMed. 8 (2002), 1189. A report on the NIH RAC model of regulation of gene transfer is in JLME 30 (2002), 381-9.

   A report of gene therapy for SCID is NS (30 Nov., 2002),  30-3. Chimeraplasty is discussed in Science 298 (2002), 2116-20. A method to attack cancer by gene therapy is discussed in NS (21 Dec., 2002), 10. Prospects of vascular proliferation by gene therapy are discussed in NatMed. 8 (2002), 1249-56. Methods to enhance the delivery of DNA by polyethylenimine are reported in PNAS 99 (2002), 16460-5. Trials of ultrasound guided stem cell removal from sheep embryos for gene therapy is reported in AJOG 187 (2002), 960-3.

   The possible extension of lifespan in humans is discussed in Population and Development Review 27 (2001), 411+. Medicine and aesthetics are discussed in Medicine, Health Care and Philosophy 2 (1999), 115-187. On regulation of gene therapy in the UK, Human Gene Therapy 12 (2001), 711-20.

   The cases of leukemia in two children in France who are gene therapy participants with SCID have raised safety questions that have lead to stopping trials like that in the USA, Nature 421 (2003), 305, 595, 678; Science 299 (2003), 320, 495, 991; NS (25 Jan., 2003), 12; NEJM 348 (2003), 255-6; BMJ 326 (2003), 181. Stem cell transplants as treatment options for SCID and other immunodeficiency diseases are discussed in Lancet 361 (2003), 541-2, 553-60.

   The promise of gene therapy is discussed in Human Gene Therapy 12 (2001), 1483-4. The need to restore public trust in gene therapy is made in J. BioLaw and Business (2001), 3-4. On gene therapy for HIV, Human Gene Therapy 12 (2001), 1013-9. Use of nonviral vectors is reviewed in Human Gene Therapy 12 (2001), 861-70.

US authorities have upheld the suspension of SCID gene therapy, NatBio 21 (2003), 217; Nature 422 (2003), 7. This is the second suspension, NatBio 20 (2002), 647, 1063, 1068-9.  On the Gelsinger case, BMJ 326 (2003), 506. The quest for genes of youth is discussed in Nature 421 (2003), 789-90; Bioethics 16 (No. 4, 2002); Milbank Quarterly 80 (2002), 155-74. Also on the ethics of using human genetic engineering, JAMA 289 (2003), 1313-4; NatBio 20 (2002), 531-2, 655. Germ-line therapy is discusse din Cooke, EF. "Germ-line engineering, freedom, and future generations", Bioethics 17 (2003), 32-58.

Systemic B-cell tumours have been eliminated by genetically targeted T lymphocytes, NatMed. 9 (2003), 279-93. Gene therapy with neprilysin reduces amyolid deposits in mice, Lancet 361 (2003), 1107. A study of the clonality of T-lymphocytes in gene therapy trials in SCID patients is NatMed. 9 (2003), 463-7. Attempts to switch off Huntington's disease by gene therapy are being considered, NS (15 March 2003), 20. Use of gene therapy against spinal muscular atrophy is considered in Canadian Biotech News 12 (27 Jan. 2003), 3-4. Possible use of RNAi is discussed in BioCentury 11 (17 March 2003), A1-8. Damaged RNA can be repaired, Nature 421 (2003), 795-6, 859-63. Correcting genes at mRNA level has been suggested for cystic fibrosis, NatBio 20 (2002), 32-3, 47-52. New techniques for chromosomal translocation products are discussed in NatMed. 9 (2003), 383-6. The safety of retroviral gene marking with a truncated NGF receptor is reviewed in NatMed. 9 (2003), 367-9. Ways to get genes into the brain are discussed in NS (22 March 2003), 16. Gene therapy for diabetes is in Lancet 361 (2003), 1443. Also on gene therapy, NatBio 20 (2002), 673, 735-8, 987-8; NEJM 348 (2003), 1282-3.

Engineering mice genomes with bacterial artificial chromosomes has been successful, NatBio 21 (2003), 443-7, 447-51. Chimeric nucleases stimulate gene targeting in human cells, Science 300 (2003), 763-4. Lengthening of telomeres and cancer is discussed in Lancet 361 (2003), 1840; Nature 423 (2003), 926-7. RNA interferences methods may not be so specific, NS (24 May 2003), 16. On research in gene therapy, GEN 23 (15 May 2003), 8, 10, 49. Bacteria genetically modified to make a drug have been given to people in a trial against inflammatory bowel disease, NS (21 June 2003), 23. Gene transfer as a tool to induce vascular growth is discussed in NatMed. 9 (2003), 694-701. A gene therapy trial against tumours is reported in NatMed. 9 (2003), 789-95.

            Papers on the ethical issues from extension of lifespan include: Juengst, ET. et al. "Biogerontology, "Anti-aging medicine", and the challenges of human enhancement", HCR 33 (July 2003), 21-30; Gems, D. "Is more life always better?", HCR 33 (July 2003),31-9; HCR 33 (July 2003), 3; NatGen 34 (2003), 237-8; Nature 424 (2003), 880-1. Certain compounds activate life-extending genes, Science 301 (2003), 1165. A special supplement is Parens E. & Knowles LP., "Reprogenetics and public policy: Reflections and Recommendations" is HCR 33 (July 2003), S1-24.

   Prolongation and extension of life by diet restriction can work in many species,  Science 301 (2003), 1679-81. Compounds in grape may promote long life,  Science 301 (2003), 1165. On extending life, NS (18 Oct. 2003), 46-9; (1 Nov. 2003), 42-6; Nature 424 (2003), 132-3; J. Heredity 94 (2003), 432. Old growth trees are being found in many places,  Science 301 (2003), 768-9. Some animals have extreme longevity,  Science 301 (2003), 611, 373-5; NS (13 Sept. 2003), 24. Biochemistry of lifespan is discussed in Nature 424 (2003), 259-60. Age can induce a switch to a hyper-recombinatorial state,  Science 301 (2003), 1908-10. On genetic enhancement, CQHE 12 (2003), 411-7. Elite athletes appear to have particular genes, NS (30 Aug. 2003), 4-5. On hair regeneration, NatMed. 9 (2003), 1257-8. On cosmetic surgery prices, The Ecologist (Sept. 2003), 44-5.

   The explanation for leukemia in two children in SCID trials, where 9 out of 10 children have had positive results is presented in Hacein-Bey-Abina, S. et al. "LMO2-associated clonal T cell proliferation in two patients after gene therapy for SCID-X1", Science 301 (2003), 415-9. Gene therapy for ALS may be ready,  NatMed. 9 (2003), 1256-7. A gene therapy trial for Parkinson disease has begun, Lancet 362 (2003), 712. Development of gene therapies for muscular dystrophy is being advanced through animal models, NatMed. 9 (2003), 997-8. In general on gene therapy accuracy,  Science 301 (2003), 400-1.

   Treatment with gentamicin appears to correct CFTR function in CF patients, NEJM 349 (2003), 1433-41. Virotherapy is reviewed in SA (Oct. 2003), 50-7.

A website for gene therapy trials in USA is www.gemcris.od.nig.gov. On gene therapy for diabetics, Amer. J. Pharmacogenomics 2 (2002), 129-34. Gene therapy prospects for ParkinsonIs disease are reviewed in Amer. J. Pharmacogenomics 2 (2002), 135-46. The clinical protocol for a phase 1 vaccine safety and chemotherapy dose-finding trial of an allogenic GM-CSF secreting breast cancer vaccine is in Human Gene Therapy 15 (2004), 313-37. Possible links of certain gene therapy to leukemia are discussed in JAMA 290 (2003), 2535.

Swiss research on descriptive bioethics is reported in Scully, JL. Et al. "Non-professionals' evaluatioNS of gene therapy ethics", SSM 58 (2004), 1415-25. Gene transfer in the reproductive tract is discussed in F&S 80 (2003), 475-84. Phase 1 trials for insertion of the gene for nerve growth factor in braiNS of Alzheimer's patients have been promising, Biotechnology News 24 (7 May 2004), 3. Also on neuronal gene therapy trials, PNAS 101 (2004), 3557-62. An explanation for the leukemia cases in two French SCID patients has been found, NEJM 350 (2004), 1679-80; Science 303 (2004), 333.
The first commercial cancer gene therapy in the world has been approved in China, APBN 8 (2004), 61. Systemic delivery of human minidystrophin to mice muscle has been reported, PNAS 101 (2004), 3581-6. A gene therapy system that responds to low oxygen in heart to avoid ischemic attack has been reported, NatBio 22 (2004), 533. A gel has been used to deliver a gene, Biotechnology News (15 April 2004), 24, 70. A multigene deficiency has been corrected in vivo in mice models, NatBio 22 (2004), 589-94.

           An interview with Gregory Stock is in Lancet 363 (2004), 1560. Gene therapy for osteogenesis imperfecta is reported in NEJM 350 (2004), 2302-4. Side effects have halted a hemophilia gene therapy trial in California after 7 patients have had minor signs of toxicity, Science 304 (2004), 1423-4. Targeted lung cancer therapy is reported in  Science 304 (2004), 1458-61; NEJM 350 (2004), 2191-3. A review of RNAi is NatGen, 36 (2004), 435. Awakening silenced genes may be a strategy for cancer therapy, JAMA 291 (2004), 2301-2. Digitoxin mimics gene therapy with CFTR in cystic fibrosis, PNAS 101 (2004), 7693-8; and reversal of CF phenotype has been achieved in a cell line, PNAS 101 (2004), 8150-5. Dendritic cell immunotherapy is reviewed in NatMed. 10 (2004), 475-80. L1 retrotransposon can disrupt transcription, Nature 429 (2004), 268-74. The blood-brain barrier is discussed in Neurobiology of Disease 16 (2004), 1-13. Norway has approved 7 gene therapy trials, Nature 429 (2004), 129; to add to the global trial data in Nature 427 (2004), 779-81.

    Human germline modification is scaled in J. Law, Medicine & Ethics 31 (Spring 2004), 164-73. A paper on research policies for genetic modification of preimplantation embryos is Milbank Quarterly 82 (2004), 195-214. Ethics of sports enhancement are discussed in French in Les Cahiers du Comite Consulttatif National d'Ethique 39 (May 2004), 7-18; also in English, Lancet 364 (2004), 573-4; Science 305 (2004), 631. Some natural gene mutations enhance muscle growth of athletes, NS (28 July 2004), 3. A book review of Elliott, C., Better than Well: American Medicine Meets the American Dream (NY: W.W. Norton, 2003, 224pp.) is in HCR 34 (May 2004), 46-7. Also on enhancement, JAMA 292 (2004), 867; NatGen 36 (2004), 661. A book review of Merchants of Immortality is NatMed. 10 (2004), 575. The bioethics of anti-ageing changes are discussed in TIBTECH 22 (2004), 218-2; BMJ 328 (2004), 1504. Lifestyle drugs are discussed in Trends in Pharmacological Sciences 25 (2004), 182-4.

    French trials of SCID gene therapy will resume after a 22 month break following leukemia cases, Nature 429 (2004), 587. RNAinterference technology is discussed in Nature 429 (2004), 792; 430 (2004), 161-4; JAMA 291 (2004), 2803-4; NatBio 22 (2004), 967, 1066; and RNAi has treated a model of spinocerebellar ataxia, NatMed. 10 (2004), 775-6, 816-27. Possible gene therapy of ALS is suggested from a mouse model, JAMA 291 (2004), 2809. On targeted therapy of tumours, NatMed. 10 (2004), 764; and gene therapy for lung cancer, Science & Medicine 9 (August 2003), 187-9. A gene required for germ cells for stem cell self-renewal has been identified, NatGen 36 (2004), 647-52. Adeno-associated virus vectors integrate at chromosome breakage sites, NatGen 36 (2004), 767-73. On gene delivery to striated muscle using AAV vectors, NatMed. 10 (2004), 828-34. Use of extra chromosomes as vectors is another option, NS (19 June 2004), 10. Gene therapy to save tissues from oxygen starvation is being suggested, NS (7 Aug. 2004), 16. In general on gene therapy, GEN 24 (15 May 2004), 39, 41.