Gene Therapy OLD News
Extracts from EEIN 1991-1994. Latest news is at the bottom. Provided by Eubios Ethics Institute , at
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There are several human trials of gene therapy currently underway in the USA, and more under review by different committeess. One trial involves inserting the gene for tumour necrosis factor into TILs which should target to cancer tumours and release the necrosis factor killing the cancer. This is the idea, we await to see if it works. It will be used in patients with malignant melanoma, and should it prove effective it will be of much more widespread use than the treatment of patients suffering with ADA deficiency. The advanced skin melanoma doesn't respond to other treatments. For a background review see SG 276-281, and Culltion, B.J. (1990) "Gene therapy: into the home stretch," Science 249: 974-976; Russell, S.J. (1990) IT 11: 196-200, 431. They hope to treat about 50 patients using this therapy (Newsweek Nov.26, 1990, p.51), and since early December have been adding one patient a week to their study (Biotechnology 8: 1233). This trial will test the safety and potential toxicity of TNF, rather than the efficiency itself, and increasing amounts of TILs will be given to each patient each week.
On the 14th September gene therapy on a child suffering from ADA deficiency began at the NIH in the USA, immediately after final approval was given by the FDA for the trial. It will be a year before proper results will be known. The report of the gene insertion in humans connected with immunotherapy appeared earlier, see Rosenberg, S.A. et al. (1990) "Gene transfer into humans - Immunotherapy of patients with advanced melanoma, using tumor-infiltrating lymphocytes modified by retroviral gene transduction," NEJM 323: 570-578.
It is expected that a child with ADA deficiency in Italy may also be treated with gene therapy. In Italy there is no government committee structure for recombinant DNA experiments unlike the extensive tiered structure in the USA. The trial only involves one child, and is associated with the US group (Nature 348 (1990), 378). There are other groups in France and the Netherlands that are nearly ready to begin also. It is important that people keep the use of somatic cell gene therapy in proportion to other therapies, and there does not need to be numerous committees established to review every medical trial.
Within a year after the identification of the cystic fibrosis gene there is a report of successful gene therapy in vitro, in epithelial cells isolated from a cystic fibrosis patient (Drumm, M.L. et al. (1990) "Correction of the cystic fibrosis defect in vitro by retrovirus-mediated gene transfer", Cell 62: 1227-1233). The expression of the normal gene confered cyclic AMP-dependent Cl channel regulation in these cells. Other groups have also proceeded with gene therapy trials (Quinton, P.M. (1990) "Righting the wrong protein," Nature 347: 226; Science 249 (1990), 1503; Lancet 336 (1990), 1224-5). In a study by Rich, D.P. et al. (1990) "Expression of cystic fibrosis transmembrane conductance regulator corrects defective chloride channel regulation in cystic fibrosis airway epithelial cells", Nature 347: 358-363; further understanding of the action of this protein, and the possibility of genetic correction are reported. There are still questions about the efficiency, the best cells to use, and the virus safety, but it is a very promising step forward and brings the prospect of gene therapy much closer than people could have imagined two years ago.
There are still major hurdles for the use of gene therapy in hemaglobin disorders. The major obstacle is the growth and selection of hematopoietic stem cells in vitro , though several animal studies show promise (Cell 63: 665-672). There is still much research on these genes and therapies at both the pharmacological level and gene level.
Liposomes have been used to provide gene transfer into muscle cells of arteries, and provide a useful model for the possible in vivo targetting of genes (Nabel, E.G. et al. (1990) "Site-specific gene expression in vivo by direct gene transfer into the arterial wall", Science 249: 1285-1288). For a review of new methods of drug delivery, such as liposome targetting see, Langer, R. (1990) "New methods of drug delivery," Science 249: 1527-1533.

A general commentary on the prospects for gene therapy is D.J.Weatherall (1991) "Gene therapy in perspective", Nature 349: 275-6. It presents some of the problems, and discusses a few of the likely applications of somatic cell gene therapy in the near future. It emphasizes the need for careful preparation before human use, to ensure efficacy and safety because any ill effects will slow down the future introduction of this technique. A note on the very early progress of the TNF gene therapy experiment is in Nature 349 (1991), 445.
The experiments aimed at gene therapy for cystic fibrosis are investigating methods of delivery to lung tissue (Scientific American (Dec 1990), 14-6). The virus used as a vector, such as adenovirus, could be aerosolised. A disadvantage of many viruses is that they require actively dividing target cells, which lung cells are not, but there are safe vectors developed. Liposomes are also being used, to bind to lung specific proteins. Another paper which is more of a review is J.R.Dorin & D.J. Porteous (1991) "Cystic fibrosis- the way forward from the gene", TIBTECH 9: 48-52.
The herpes simplex virus is being engineered to construct a possible vector for neural gene therapy (Scientific American (Jan 1991), 13). There is a need for a vector if some of the many neurological diseases can be treated by gene therapy, and this virus can express genes without requiring the cell to reproduce, unlike retroviruses. It is also very large (containing about 70 genes), so that large genes could be carried, if it should prove safe.
Another vector that may be possible to use is the envelopes of viruses, see R.Blumenthal & A.Loyter (1991) "Reconstituted viral envelopes- 'Trojan Horses' for drug delivery and gene therapy?", TIBTECH 9: 41-5.
A paper describing the use of particle bombardment for gene transfer to mammalian cells, in particular human cell lines, is N.S.Yang et al. (1990) "In vivo and in vitro gene transfer to mammalian somatic cells by particle bombardment" PNAS 87: 9568-72. DNA-coated gold particles were used on mice and rat tissues in vivo, and in human cell lines. This type of biolistics was developed first in plants, but is proving effective for animal gene delivery also.
The frequency of homologous recombination has been found to widely vary among different eucaryotes. The use of homologous gene replacement for gene therapy is desirable but is hampered by the low frequency of homologous comparted with nonhomologous recombination. In lower eucaryotes the frequency of homologous recombination and its efficiency are much higher, as illustrated by a recent paper, M.G.S.Lee & L.H.T.Van der Ploeg (1990) "Homologous recombination and stable transfection in the parasitic protozoan Trypanosoma brucei ", Science 250: 1583-6. Several other protozoa have also been shown to have a high efficiency of homologous recombination.

The Gene Therapy Subcommittee of the RAC of the NIH has recommended approval for a third somatic cell gene insertion protocol. It will involve inserting the neomycin marker gene into cancer cells from the bone marrow to test where cancer cells which reappear after adoptive immunotherapy originate from; Biotechnology 9 (1991), 318.
The French National Bioethics Council has approved a gene therapy trial on ten patients suffering from "incurable" skin melanoma, using similar methods to those being used in the washington trial; NS (6 April 1991), 14. On the question of the wording of a US consent form a brief comment is in Science 251: 1019.
A paper from a study on rats is T.D.Palmer et al. (1991) "Genetically modified skin fibroblasts persist long after transplantation but gradually inactivate introduced genes", PNAS 88: 1330-4. The new cells survived in grafts but the gene expression for ADA and neomycin phosphotransferase was lost. More success was found when the ADA gene was inserted into human blood lymphocytes, which survived in SCID mice; G.Ferrari et al. (1991) "An in vivo model of somatic cell gene therapy for human severe combined immunodeficiency", Science 251: 1363-6.
Another animal experiment involving gene delivery is R.S. Williams et al. (1991) "Introduction of foreign genes into tissues of living mice by DNA-coated microprojectiles", PNAS 88: 2726-30. The genes (for luciferase) were expressed in liver and skin cells after microprojectile transfer in the living animals. Two proposals are in a paper by M.A.Goldsmith in Perspectives in Biology and Medicine (1991) concerning the use of gene immunisation against AIDS (not a new idea), but including a speculative method; Biotechnology 9 (1991), 211. A system for site specific gene insertion is described in S.O'Gorman et al. (1991) "Recombinase-mediated gene activation and site-specific integration in mammalian cells", Science 251: 1351-5.
The understanding of cystic fibrosis is slowly moving, several papers highlighting the role of the chloride channel protein include: gene expression in insect cells, Cell 64: 681-91; Nature 350 (1991), 277-8. The genetic determinants in general are discussed in Lancet 337 (1991), 631-4 & 623.

For general comments on gene therapy see a conference report in Lancet 337: 1277-8; and for a review see R.A. Fleischman, "Southwestern internal medicine conference: human gene therapy", Amer.J.Med.Sci. 301: 353-63. See also O. Valabreque-Wurzburger, "Introduction of modified genetic material into human subjects genotherapy", IJB 1 (Dec 1990), 245-63 (French).
A vector to target lung cells is described by M.A.Rosenfield et al., "Adenovirus-mediated transfer of a recombinant 1-antitrypsin gene to the lung epithelium in vivo", Science 252: 431-4, 374; Lancet 337: 1155. The respiratory epithelia is the target cell for any gene therapy attempts to treat cystic fibrosis and 1-antitrypsin. The experiment was conducted in rat cells in vitro and in vivo . The safety of adenoviral vectors need to be addressed.
Further results from the NIH gene therapy trials are presented in K.Culver et al., "Lymphocytes as cellular vehicles for gene therpay in mouse and man", PNAS 88: 3155-9. The advantages of lymphocytes as vehicles include their availability from peripheral blood, ease of manipulation in in vitro culture, also they are more differentiated than bone marrow cells, so are not so susceptable to inactivation through the steps of differentiation, memory lymphocytes proliferate when exposed to antigen, and some lymphocytes will target to sites in the body. The progress from the ADA deficiency gene therapy trials appears to be positive so far; JAMA 265: 2311-2.
Results of in vitro studies in a mouse-human hybrid cell line are in E.G. Sheseley et al., "Correction of a human ßs-globin gene by gene targeting", PNAS 88: 4294-8. They corrected the ßs to a ßa gene, with the aid of a neomycin resistance gene. On the use of genetically engineered viruses as a method of disrupting disease see R.L.Martuza et al., "Experimental therapy of human glioma by means of a genetically engineered virus mutant", Science 252: 854-6.
On some animal experiments see R.N.Kitsis et al., "Hormonal modulation of a gene injected into rat heart in vivo ", PNAS 88: 4138-42; and K.G.Golic, "Site-specific recombination between homologous chromosomes in Drosophila ", Science 252: 958-61.

The NIH Recombinant DNA Committee (RAC) has approved several gene therapy trials, and many more are expected; Biotechnology 9: 602. There are still two committees for the examination of protocols, which has gained public confidence, but some have questions about the need for many committees. Three experiments have been recently approved by the NIH RAC; NS (10 Aug 1991), 13. These include another trial for the insertion of TNF genes in cancer patients; a trial using thymidine kinase gene from Herpes Simplex virus in a treatment for ovarian cancer on women who have not responded to surgery or chemotherapy; and to insert the gene for low density lipoprotein receptor into liver cells of patients with inherited familial hypercholesterolaemia (successful trials in rabbits have been performed).
A general comment on gene therapy appears in the Canadian magazine Maclean's (15 July 1991), 32-9, with comment on the hope for cystic fibrosis patients.
One of the methods of gene delivery is cell grafting. A review on this topic is F.H. Gage et al., "Genetically modified cells: applications for intracerebral grafting", TINS 14: 328-33. Also see J.A. Hubbell et al., "Endothelial cell selective materials for tissue engineering in the vascular graft via a new receptor", Biotechnology 9: 568-72. A cell type specific receptor was identified which may be useful for the establishment of grafts. The use of retrotransposons for gene transfer to murine and human cells is reported in R.F. Cook et al., "Retro-transposon gene engineering", Biotechnology 9: 748-51.
There have been some scientists advocating the use of gene therapy for AIDS; Biotechnology 9: 694; NS (29 June 1991), 18. Several possible ideas are under consideration. Another possibility for gene therapy is in the disease chronic myelogenous leukaemia; NS (10 Aug 1991), 21. A comment on the therapeutic potential of triplet DNA for therapy and gene control is in Science 252; 1374-5.

The US regulatory authorities, the FDA and the RAC, are considering the regulation of gene therapy and insertion procedures. Some streamlining has been suggested; Biotechnology 9: 917; Science 253: 624-5; Nature 353: 591. A subpanel of the NIH Human Gene Therapy Subcommittee is starting to examine the issues of germ cell gene therapy.
A protocol by J. Wilson of the University of Michigan was recently approved in the USA by the subcommittee of the gene therapy committee. It is to conduct trials of liver gene therapy, involving removal of a portion of the liver, in vitro genetic transfer, then to retransplant the liver back into the patients, as a treatment for familial hypercholesterolemia; Science 253: 624. On in vivo retroviral gene transfer into mouse hepatocytes, while a portion of the liver was isolated from general circulation, see PNAS 88: 8377-81. It was more successful at obtaining expression of the gene than in vitro gene transfer, and transplanting the transformed cells.
Gene therapy as use in cancer therapy continues, using insertions of the genes tumour necrosis factor, and interleukin-2; Science 253: 624. A trial of gene insertion underway in St. Judes Hospital, Memphis, TN, involves neomycin resistance marker genes to trace the routes of cancer cells from the bone marrow, which was the first non-NIH clinical trial approved. Also approved by the subcommittee of the gene therapy committee, however rejected by the full RAC; Nature 353: 591; was a protocol to put a marker onto ovarian cancer cells to make the cancer cells sensitive to the drug gancyclovir. More animal research is required. A new treatment protocol that could work for treating hepatocellular carcinoma is described in B.E. Huber et al., "Retroviral-mediated gene therapy for the treatment of hepatocellular carcinoma: An innovative approach for cancer therapy", PNAS 88: 8039-43. The idea is to exploit the transcriptional differences between normal and neoplastic cells to selectively kill cancer cells. The gene transferred, which should be activated in neoplastic cells, encodes an enzyme which will convert a prodrug into the active form, making it active only around cells expressing the gene (i.e. the neoplastic cells). However, this study only reports on in vitro results, and the animal trials are still underway.
Experiments for the general preparation for possible cystic fibrosis gene therapy include; J. A. Tabcharani et al., "Phosphorylation-regulated Cl- channel in CHO cells stably expressing the cystic fibrosis gene", Nature 352: 628-31. Transfer of the cystic fibrosis transmembrane conductance regulator (CFTR) gene to rats found that there was some tissue specificity in expression; A.E.O. Trezise & M. Buchwald, "In vivo cell-specific expression of the cystic fibrosis transmembrane conductance regulator", Nature 353: 434-7. Spermatoids expressed CFTR, suggesting a reason why male CF patients are infertile.
A method using aerosol sprays to deliver genes into rabbit lungs is reported in Clinical Research (May 1992); Science 253: 964-5. Positively charged liposomes were used to transfer alpha-1-antitrypsin genes.
Gene therapy for muscular diseases seems more possible after the report G. Acsadi et al., "Human dystrophin expression in mdx mice after intramuscular injection of DNA constructs", Nature 352: 815-8. The complete dystrophin gene was expressed in myofibres, but as a successful therapy a large number of myofibres would need to be transferred to patients. The efficiency of gene transfer needs to be improved before clinical trials. See comment in Nature 352: 757-8.
Treatment of blood disorders is one major target of gene therapy. See S.-N. Yao et al., "Expression of human factor IX in rat capillary endothelial cells: Toward somatic gene therapy for hemophilia B", PNAS 88: 8101-5.
Thoughts about the use of gene transfer as a therapy for atherosclerosis gives evidence of the wide variety of diseases for which gene therapy may be useful in the future. See E.M. Rubin et al., "Inhibition of early atherogenesis in transgenic mice by human apolipoprotein AI", Nature 353: 265-7. However, long term studies are needed to test the other effects of high apolipoprotein AI expression.
On the general improvement of directed gene targeting see Science 253: 1110-7. On the use of antisense RNA see Science 253: 510-1, and applications in a broad range of genetic engineering. On antisense and gene therapy see J. Amer. Society of Microbiology 57: 346-7. On gene targeting to destroy the function of an interleukin-2 gene in mice see Nature 352: 621-4. On erythropoietin gene expression in mice see PNAS 88: 8725-9. On the detection of somatic DNA recombination in transgenic mouse brains, and its relationship to nervous system development, see Science 254: 81-9.

A detailed description of the gene therapy trial underway in the NIH to attempt to immunise a terminally-ill patient against their own cancer; GEN (Nov/Dec 1991), 1, 52. It is an experimental strategy involving the removal of tumour cells from the patient, and attempting to enhance their sensitivity to immune system attack. It is an extension of the work involving the insertion of a gene for tumor necrosis factor (TNF) (EEIN 1: 81); Science 254: 372; Biotechnology 9: 1037; JAMA 266: 2193, 2668-9. 15 patients will be treated with TNF gene insertions, and another 15 with IL-2 genes.
Currently there have been 6 gene transfer and 6 gene therapy trials approved in the USA, and another 7 are awaiting approval in early 1992. The FDA is preparing to issue guidelines for gene therapy experiments and "products", which would also apply to commercial uses.
Another variation of this for cancer treatment may be using IL-4 secreting tumor cells, as has worked in mice; P.T. Golumbek, et al., "Treatment of established renal cancer by tumor cells engineered to secrete interleukin-4", Science 254: 713-6. For reviews of current research and applications see Nature 354: 429; M.H. Steinberg, "Prospects of gene therapy for hemoglobinpathies", Amer. J. Medical Sciences 302: 298-303.
A new technique for gene therapy gene delivery involves the injection of mRNA or plasmid DNA into different tissues in a living mouse; GEN (Nov/Dec 1991), 48. It has been developed by researchers in the USA. The use of retroelement particles, such as retroviruses to deliver genes is discussed in TIBTECH 9: 303-9. Another route for delivery is via the lungs (EEIN 1: 81), as has been developed for peptides and proteins; TIBTECH 9: 284-9; Biotechnology 9: 1326-31. A general review of stem cells is D.W. Golde, "The stem cell", in SA (Dec 1991), 36-43.
On the delivery of genes into muscle cells (EEIN 1: 81), see comment in Science 254: 1455-6, upon the results of two further papers on this route; E. Barr & J.M. Leiden, "Systemic delivery of recombinant proteins by genetically modified myoblasts", Science 254: 1507-9; J. Dhawan et al., "Systemic delivery of human growth hormone by injection of genetically engineered myoblasts", Science 254: 1509-12. After delivery of the gene for human growth hormone in the myoblasts which were injected into muscle, growth hormone could be detected for 3 months in the serum of the mice. These two papers come from different US laboratories, using similar approaches. Myoblasts are immature muscle cells, and may be useful vectors for gene transfer because of their survival and reproduction in hosts. A further step in gene therapy would be expression of genes after injection of DNA into muscle, something achieved in 1990 in animals.
Related to a religious view on the limits of genetic manipulation is a paper by A.S. Moraczewski, "The human genome project and the Catholic church", IJB 3: 229-34. It briefly covers several related issues to the use of genetic information, and draws on Papal statements on the distinction between therapeutic and nontherapeutic gene manipulation, rejecting nontherapeutic manipulation. Another paper, from a different Christian tradition is G.R. Dunstan, "Gene therapy, human nature and the churches", IJB 3: 235-40. He rejects the right for a human to inherit an unmanipulated genome, because they are not yet persons. However, this does not mean it should be allowed, we need to look at the child's interest.
A summary of the Canadian guidelines for research on somatic cell gene therapy, and discussion are in IJB 3: 241-4.
Gene therapy of skin cells may be useful for many diseases. A model for preclinical tests is described in P.K.A. Jensen & L. Bolund, "Tissue culture of human epidermal keratinocytes: a differentiating model system for gene testing and somatic gene therapy", J. Cell Science 100: 255-9.
Several animal experiments involving expression of transferred genes that have possible clinical relevance for human gene therapy have been reported. It may be possible to improve transplantation tolerance by genetic engineering of immune cells; G.E. Shafer et al., "Expression of a swine class II gene in murine bone marrow hematopoietic cells by retroviral-mediated gene transfer", PNAS 88: 9760-4. For myotonia see K. Stenmeyer et al., "Inactivation of muscle chloride channel by transposon insertion in myotonic mice", Nature 354: 304-8.

The Clothier report on gene therapy has been released in the UK and it recommends the use of somatic cell gene therapy in the UK; NS (25 Jan 1991), 18. The report recommends a moratorium on germline gene therapy until the treatment is safe, and ethical issues are discussed. The UK government is seeking more opinions, until May 18; Lancet 339: 238; Nature 355: 190, 286; BMJ 304: 201.
The commercial development of gene therapy is featured in an article; M. Blestone, "Genes in a bottle", Biotechnology 10: 132-6. A variety of approaches are in research stage, including more generally and easily transferable vectors. Approaches for in vivo treatments are being developed for cystic fibrosis, and other diseases. It is expected that they may not get beyond phase 1 clinical trials until the end of this decade, with this in vivo approach. The paper includes a list of some US companies specialising in gene therapy.
The first commercial test of gene therapy was recently approved in the USA; New York Times (14 Feb 1991), D1. The test involves genetically modified cells to fight AIDS. A general comment on gene therapy is H.M. Schmeck, "A new era of gene therapy", FDA Consumer (Dec 1991), 14-9.
The possibility of using gene therapy to treat cystic fibrosis is progressing, with the results of animal experiments; M.A. Rosenfeld et al., "In vivo transfer of human cystic fibrosis transmembrane conductance regulator gene to the airway epithelium", Cell 68: 143-55. NS (18 Jan 1991), 9; Nature 354 (1991), 503-4, 526-8; Science 255: 289. The used the adenovirus vector to transfer the gene in vivo in rats, and they suggest it is ready for human trials.
On progress to make a new pancreas beta cell to treat insulin-dependent diabetes see Science 255: 282-3. On the results of animal experiments see; J.R. Chrowdhury et al., "Long term improvement of hypercholesterolemia after ex vivo gene therapy in lDLR-deficient rabbits", Science 254 (1991), 1802-5 (see EEIN 1: 81 for details of an approved human trial). On muscle disease and gene switching see JAMA 267: 337-8.
A discussion of the ethical issues of genetic therapy is N.J. Zolar, "Prospects for "genetic therapy" - can a person benefit from being altered?", Bioethics 5: 275-288; J. P. Kahn, "Genetic harm: bitten by the body that keeps you?", Bioethics 5: 289-308, followed by responses of each author to each others paper; p. 309-317.
On scientific advances in gene transfer; Biotechnology 10: 17. On selectable genes for markers; F. Schwartz et al., "A dominant positive and negative selectable gene for use in mammalian cells", PNAS 88: 10416-20.

The debate over the difference between therapeutic human gene therapy and enhancement gene "therapy" is addressed in a number of recent papers. It was also the topic of one of the sessions at the Houston conference on Genetics, Religion and Ethics, discussed above. We can question where the boundary between therapy and enhancement lies. A summary of objections to enhancement gene transfer is in an editorial in Human Gene Therapy 3: 1-2. The relationship between use of gene therapy for enhancement and altering the standards used for selective abortion is in S.G. Post, "Selective abortion and gene therapy: reflections on human limits", Human Gene Therapy 2 (1991), 299-33.
Another question is where the boundary between somatic cell and germ-line gene therapy lies. The December (1991) edition of the Journal of Medicine and Philosophy focused on human germ-line engineering. It includes papers by E.T. Juengst, B.K. Zimmerman, K. Nolan, M. Lappe, R. Moseley, A. Mauron & J.M. Thevoz, E.M. Berger & B.M. Gert, and W.M. Monford. The topic of germ-line genetic engineering remains at an early stage of ethical debate, and these papers look at some of the current arguments in favour of it (e.g. medical utility, necessity, efficiency, parental autonomy and scientific freedom) and arguments against (e.g. scientific uncertainty, clinical risks, slippery slope to enhancement, lack of consent from future generations, allocation of resources and integrity of genetic patrimony (what I called genetic freedom in SG 258-260)). We must ask what the goals of medicine are. Another key question that we need to examine is our view of what is perceived to be "natural", and what is not, and this is one of my current research themes if anyone else is also looking at this please contact me regarding this.
A review of the safety of gene transfer is K. Cornetta et al., "Safety issues related to retroviral-mediated gene transfer in humans", Human Gene Therapy 2(1991), 5-14. The legal liability associated with the use of gene therapy is discussed in J.G. Palmer, "Liability considerations presented by gene therapy", Human Gene Therapy 2(1991), 235-42. The effect on future generations raises questions about the limits of liability.
Some of the key finding of the Clothier report on gene therapy (EEIN 2: 24; NS (15 Feb 1992), 5) are reproduced in BME (Feb 1992), 8-10. There appears to be public support for gene therapy in many countries (including Japan, as described in my book advertised on the back cover of this edition), and a list of international statements made on gene therapy is included in the paper; L. Walters, "Human gene therapy: ethics and public policy", Human Gene Therapy 2(1991), 115-22.
The RAC of the NIH has approved two protocols by commercial companies for clinical trials of gene therapy; Biotechnology 10: 368; SA (Feb 1992), 85-6. One trial involves a suicide gene, a gene for hygromycin phosphotransferase fused to herpes virus thymidine kinase, which will be inserted into T-cells from AIDS patients with non-Hodgkin's lymphoma. Several other trials are also discussed there. The panel also approved the first clinical trial of in vivo gene therapy; Biotechnology 10: 369. The trial will involve injection of tumour nodules in patients with advanced metastatic melanoma (the most lethal form of skin cancer) with DNA encoding HLA-B7, via a liposome carrier vector. The idea is that such a label for an HLA antigen, will show the body where the tumour is, so that the body can destroy those cells. About 12-15 patients will be involved, who are unresponsive to other forms of treatment and who have less than one year's life expectancy.
Scientific papers on gene therapy, and animal trials include: B. Quantin et al., "Adenovirus as an expression vector in muscle cells in vivo", PNAS 89: 2581-4; C.M. Lynch et al., "Long-term expression of human adenosine deaminase in vascular smooth muscle cells of rats: A model for gene therapy", PNAS 89: 1138-42; D.Tang et al., "Genetic immunisation is a simple method for eliciting an immune response", Nature 356: 152-4. Treatment for muscular dystrophy may be closer, following the use of a shortened version of the dystrophin gene into the mouse model (mdx mice) of Duschenne muscular dystrophy; Human Molecular Genetics (April 1992); NS (28 March 1991), 24. They described good improvement, with only 3-5% of muscle fibers damaged versus 2-3% in normal mice, and 19-28% in mdx mice without the gene insert. See also the genetic markers section on DMD.
A review of applications to cancer is A.A. Gutierrez et al., "Gene therapy for cancer", Lancet 339: 715-21. Research on gene delivery to stem cells, which is the goal of therapy to alleviate many blood and immune disorders, is described in Science 255: 1072. The use of genetically engineered cells in skin grafts is discussed in NS (22 Feb 1992), 11. Papers on cystic fibrosis therapy and protein are J. Pediatrics 120: 337-49; Cell 68: 809-16.
The method that gene therapy is regulated in the USA has recently been simplified. A discussion on the basis for the FDA "points to consider for gene transfer" is in S.L. Epstein, "Regulatory concerns in human gene therapy", Human Gene Therapy 2(1991), 243-9. The points to consider for human somatic cell therapy and gene therapy released by the FDA in 1991 are in Human Gene Therapy 2 (1991), 251-6. The RAC gene therapy subcommittee voted itself out of existence in february. The full RAC advisory committee has enough experience to examine applications themselves and it should shorten the review time; Nature 355: 664. A review from a personal point of view, on the way the RAC and its members approved gene therapy clinical trials is I.H. Carmen, "Debates, divisions, and decisions: Recombinant DNA advisory committee (RAC) authorization of the first human gene transfer experiments", AJHG 50: 245-60. The different members approached the RAC with different outlooks.

In Japan, a recent committee report has urged the government to allow gene therapy to begin; Japan Times (23 June 1992), 2. In Nagoya, there is an application to perform gene therapy to cure a malignant brain tumour. The response and lag time for regulations to be developed is unknown. Gene therapy in Europe has begun, and is discussed in Biotechnology 10: 494, the Italian trial is the first to use bone marrow stem cells for ADA deficiency treatment; Nature 356: 465.
Recently, a trial in Michigan began, using injection of DNA directly in vivo in human clinical trials, aimed at a malignant melanoma; Science 256: 305; BMJ 304: 1202-3. Another trial recently approved, involves injection of a gene in a herpes virus vector into a brain tumor; Science 256: 1513. On gene therapy for cancer see Lancet 339: 1109-10.
Two major reviews of gene therapy have been published, W.F. Anderson, "Human gene therapy", Science 256: 808-13, which lists the currently approved gene therapy trials in the world, and discusses the broad impact; A.D. Miller, "Human gene therapy comes of age", Nature 357: 455-60, which is purely technical. A discussion of animal models used in gene therapy research is in Science 256: 772-3. A new vector which carries the DNA on the outside, using an antibody tag, is described in Science 256: 445. For gene targeting in mice, PNAS 89: 4471-5, plus papers in the animal experiments section on other embryonic stem cell targetted genetic engineering. In zebrafish, cell transplants can survive in the germline, S. Lin et al., "Production of germ-line chimeras in zebrafish by cell transplants from genetically pigmented to albino embryos", PNAS 89: 4519-23.
Comments on the increasing number of gene therapy trials is also in JAMA 267: 2854-5. See also, K.W. Culver et al., "In vivo gene transfer with retoviral vector-producer cells for treatment of experimental brain tumors", Science 256: 1550-2; S.-N. Yao & K. Kurachi, "Expression of human factor IX in mice after injection of genetically modified myoblasts", PNAS 3357-61. On targeting genes in the immune system see Science 256: 483.

Three critiques on the UK Clothier report on gene therapy are in BME (June 1992), 13-20. Criticisms include the need for a more balanced committee, the reductionism of genetics and definitions of disability, and the rather naive idea that human gene therapy adds no new ethical issues.
The first gene therapy trial for brain cancer which will be performed by Genetic Therapy Inc. is expected to begin very soon, following approval in June; GEN 12(10), 19. The trial involves the gene thymidine kinase (TK), which when inserted into cells makes them sensitive to a drug, gangiclovir. The drug should not affect normal brain cells, but will kill the vector cells and cells that the TK gene has been transferred to. They also received RAC approval for a trial involving interleukin-2 for treatment of neuroblastoma .
A report on the direct DNA injection in the Michigan trial for malignant melanoma is in Science 256: 1628 (EEIN 2: 52).
The approval of a trial of gene therapy by the FDA without RAC approval, from a company Viagene is reported in Nature 357: 615. If companies receive no federal funds they do not need RAC approval, and other companies are expected to follow. This trial involves a proposed genetic HIV vaccine . On the commercial developments in gene therapy a review of research; SA (June 1992), 81-2.
A committee of the Ministry of Health and Welfare in Japan has recommended the establishment of guidelines and creation of a central committee to review gene therapy trial applications in Japan; Nature 358: 6. However, we can say at long last - it has been recommended by many for a decade or more. Still different ministries have there own committees and often long review times are required.
A report on a recent NIH conference examining the prospects of gene therapy for treatment of hemophilia is in GEN 12(6), 26. Papers on the development of gene targetting techniques are in PNAS 89: 5128-32; Molecular & Cellular Biology 12: 3365-71.
The development of tissue engineering is discussed in S.M. Edgington, "3-D biotech: tissue engineering", Biotechnology 10: 855-8. The injection of healthy myoblasts as a treatment for muscular dystrophy is reported in Science 257: 738; but it is under investigation because the reported results are very good; Science 257: 472-4.
A general system for drug or gene delivery is using liposomes. The commercial development of liposomes is discussed in Biotechnology 10: 732-3. Papers on the use of adenoviruses and herpesvirus as gene therapy vectors are in Nature Genetics 1: 372-84; Nature 358: 519.
The NIH is reexamining the trials of growth hormone on healthy short children following much criticism for its earlier approval; Science 257: 739; Nature 358: 4, and it is being reviewed.
A paper on the ethics of germ-line therapy is J.C. Fletcher & W.F. Anderson, "Germ-line gene therapy: a new stage of debate", Law, Medicine & Health Care 20: 26-39.

As reported in the last issue (EEIN 2: 67), a system or guidelines for examination of human gene therapy trials in Japan is being developed; BMJ 305: 442. The first application for a clinical trial was made in December 1991, but we are still waiting to see when the guidelines will be made.
The NIH has considered a trial for the insertion of a retrovirus carrying a functioning p53 gene or an antisense version of the k-ras gene in an attempt to treat small cell lung cancer , at the MD Anderson Cancer Center at Houston; Science 257: 1467; BMJ 305: 792. The current cure rate is 14%, the same for the last 25 years, whereas in laboratory studies the researchers have achieved an 80% cure rate in mice. Another approach to treating cancer is to eliminate cancer causing genes from the tumour cells, D.D. Von Hoff et al., "Elimination of extrachromosomally amplified myc genes from human tumor cells reduces their tumorigenicity", PNAS 89: 8165-9.
Children with acute liver failure are to receive genetically engineered liver cells, following successful mouse trials; NS (10 Oct 1992), 16. This trial will be at Baylor College, Texas, and the liver cells will be making alpha-1-antitrypsin . Further research is underway to treat phenylketonuria.
A general article describing research at the NIH laboratory, and reviewing the book Steven Rosenberg, The Transformed Cell, is in Newsweek (19 Oct 1992), 48-50. It discusses the hopes for the gene therapy trials using tumour-infiltrating lymphocytes with inserted TNF or IL-2 genes to attempt to treat malignant melanoma. A broad listing of the gene therapy research at the NIH is in Nature 359: 188-9. They include research on treatment of cancer, AIDS, genetic diseases and cardiovascular diseases. It also lists the recipients of gene therapy and cancer projects in the USA. In Britain, researchers announced that they expect that melanoma vaccine gene therapy trials could begin at the end of 1993; NS (26 Sept 1992), 7.
A general review on diabetes , and the potential for gene therapy is C.B. Newgard, "Cellular engineering for the treatment of metabolic disorders: prospects for therapy in diabetes", Biotechnology 10: 1112-20. Letters on the use of myoblast transplants are in Science 257: 1329-30.
The NIH trials of human growth hormone to short children not suffering from growth hormone deficiency are being reviewed (EEIN 2: 67), Lancet 340: 478; BMJ 305: 492; NS (15 Aug 1992), 7. No new children are being enroled in the studies. On delayed puberty in children, which is treated, see BMJ 305: 790.
The safety of human gene therapy and monkey trials are discussed in Science 257: 1854. Technical papers include S. Fitzpatrick-McElligott, "Gene transfer to tumor-infiltrating lymphocytes and other mammalian somatic cells by microprojectile bombardment", Biotechnology 10: 1036-40. She used a helium gas acceleration system and enhanced cell viability and transformation efficiency. A method for achieving delivery of proteins into the brain by passive lipophilic transport is N. Bodor et al., "A strategy for delivering peptides into the central nervous system by sequential metabolism", Science 257: 1698-1700. Precise gene targeting in Chinese Hamster Ovary cells is in S. Fukushige & B. Sauer, "Genomic targeting with a positive-selection lox integration vector allows highly reproducible gene expression in mammalian cells", PNAS 89: 7905-9.

The gene therapy trial described in the last issue (EEIN 2: 81), to interfere with the activity of the k-ras oncogene and to produce the p53 suppressor gene protein has been recommended for approval by the NIH RAC; Biotechnology 10: 1408-9. The total number of recommended trials as of October was 11 for direct therapy and 21 for gene marking studies. Worldwide there have been 18 trials attempting therapy. A discussion of the trials in the USA, including the trial against AIDS, is also in Science 258: 744-6. A scientific report of trials by S.A. Rosenburg on gene therapy for cancer treatment is in JAMA 268: 2416-9. A review of S. Rosenburg's book, The Transformed Cell, is in Nature 360: 219-20. Meanwhile, he has been criticised for commencing a recent trial of gene therapy with what others consider to be scant data; Nature 360: 399-400.
A review on malignant melanoma including treatment approaches is in Lancet 340: 948-51. A revised model of human growth, suggesting humans grow in spurts and 90-95% of infant life is free of growth, called the saltation and stasis model is in Science 258: 801-3. The positive results of a mice study on expression of factor IX protein following in vivo transplantation of primary myoblasts are in PNAS 89: 10892-5.
A paper on the public acceptance of gene therapy is D. Macer, "Public acceptance of human gene therapy and perceptions of human genetic manipulation", Human Gene Therapy 3: 511-8. It includes some results of the questionnaires that were published in Attitudes to Genetic Engineering: Japanese and International Comparisons (see back page), plus some further interpretation. The University of Pennsylvania will open the world's first gene therapy institute in March 1993.
The results of a telephone survey of 1,000 public in the USA conducted by Louis Harris & Associates for the March of Dimes (EEIN 2: 71) reveal 89% approve of using gene therapy to treat genetic diseases, 47% strongly approve and 41% approve, with 8% disapproving. There is quite strong support also for germ-line gene therapy, and enhancement. 43% and 42% would approve of using gene therapy to improve the physical characters or intelligence level that children would inherit, respectively. 66% would approve of using gene therapy to prevent children inheriting a non-fatal disease, a drop from 77% in 1986; compared to 79% who would approve of using it to prevent children inheriting a usually fatal disease (from 84%).
Related is a paper on delivery of boron to kill tumours using liposomes; PNAS 89: 9039-43. The construction of biodegradable matrices which allow for a controlled release of antibodies in vivo is described in Biotechnology 10: 1446-9.

There has been hot debate about whether dying patients should receive unproven gene therapy, following B. Healy, NIH Director's, approval of a test on a woman with a brain tumour without seeking the advice of the RAC; Science 259: 172, 452; Nature 361: 196. Three trials against cystic fibrosis were approved; Biotechnology 11: 28-9. The FDA has also been persuaded by compassionate arguments to give patients broader access to gene therapy; Science 258 (1992), 1728. Also on gene therapy in the USA see Science 259: 303; Human Gene Therapy 3 (1992), 251-2, 277-8, 279-84, 459-50. The number of patients involved in the 15 gene therapy/transfer trials in the USA is listed in Human Gene Therapy 3 (1992), 595. The University of Pennsylvania has established a new Institute for Human Gene Therapy; Nature 360 (1992), 501.
The Boston-based Council for Responsible Genetics has criticised the debate over the ethics of germ-line gene therapy, and considers it is unconditionally opposed to germ-line gene therapy or manipulation; geneWATCH (Nov 92), 6. An editorial on germ-line gene therapy is in Human Gene Therapy 3 (1992), 361-3. Also on the debate, Human Gene Therapy 3 (1992), 359-60.
The first trial of gene therapy to be approved in the UK , to treat a sufferer of ADA deficiency, will begin soon; NS (6 Feb 1993), 8. This follows calls for trials to begin, NS (12 Dec 1992), 3-4. Germany has also approved its first gene therapy trials, a trial against cancer; Nature 360 (1992), 702. Because of strict genetic engineering laws this came as a little surprise, but the trial was approved in three months without problems. The gene for IL-2 will be inserted by electroporation into fibroblasts, these fibroblasts will be mixed with tumour cells from the patient, irradiated, then injected as a vaccine.
The successful results of company trials by Viagene of a genetic vaccine against cancer in mice appear to be due to stimulated production of cytotoxic T-lymphocytes; GEN (Dec 92), 32. In one trial animals were vaccinated with retroviral vectors containing specific cancer-associated sequences, and the animals showed immunological protection against viable cancer cells. The possibility of using gene therapy for cardiac disease is reviewed in JAMA 268 (1992), 3285-6.
The cystic fibrosis transmembrane conductance regulator has been found to form an aqueous channel; Science 258 (1992), 1477-9. A report on how a virus has been modified for the gene therapy trial to treat cystic fibrosis is in NS (12 Dec 1992), 5. The gene therapy trial is the first one to use adenovirus, and begun in early 1993; Science 258 (1992), 1728; Nature 361: 5. A paper on aerosol gene delivery in vivo in mice is in PNAS 89 (1992), 11277-81. See also Human Gene Therapy 3 (1992), 253-66.
Papers on the science of gene therapy include: PNAS 89 (1992), 11111-2; Science 259: 234-8; BioEssays 14 (1992), 495-500; J.H. Wolfe et al., "Reversal of pathology in murine mucopolysacchari-dosis type VII by somatic cell gene transfer", Nature 360 (1992), 749-53; M. Grossman et al., "Transplantation of genetically modified autologous hepatocytes into nonhuman primates: Feasibility and short-term toxicity", Human Gene Therapy 3 (1992), 501-10; on reducing HIV production, Human Gene Therapy 3 (1992), 461-9; Human Gene Therapy 3 (1992), 471-7; F.L. Moolten & L.A. Cupples, "A model for predicting the risk of cancer consequent to retroviral gene therapy", Human Gene Therapy 3 (1992), 479-86; using herpes virus as a vector for the human central nervous system, Human Gene Therapy 3 (1992), 487-99; using liposome-DNA complexes, Human Gene Therapy 3 (1992), 267-75. A paper reporting the identification of the bone marrow stem cell is S. Huang & L.W.M.M. Terstappen, "Formation of haematopoietic micro-environment and haematopoietic stem cells from single human bone marrow stem cells", Nature 360 (1992), 745-9, 709.
A report from a conference on Gene Therapy of Cancer held in San Diego, California, is in GEN (Jan 1993), 1, 17, 19. There are many promising results from animal cells, and more human trials planned. The introduction of normal tumour suppressor genes may be one promising approach, but also the use of ribozymes (catalytic RNA) is being tested.

A special gene therapy committee of the Ministry of health and Welfare in Japan has issued guidelines for gene therapy trials; Nature 362: 684. The Ministry of Education is still to clarify the position for university hospitals where research is being done, but it is expected that they will allow somatic cell therapy when applications come, later this year. The committee was paid for out of the AIDS budget, and trials of a genetic AIDS vaccine being tested by Viagene in the USA may be one of the first to be tried in Japan. There are also plans for a transfer of interferon genes to brain cells to treat brain tumours. The guidelines rule out germ-line therapy, and limit cases to terminal illnesses without effective therapy. However, they only require verbal informed consent, not written consent, that may be determined by local hospitals policies. The guidelines are available in Japanese, but contain no references.
The UK government has set up a gene therapy advisory committee, though a trial on a 7 month baby suffering from ADA deficiency has already been approved (EEIN 3: 24; BMJ 306: 658). There is another trial under examination for cystic fibrosis therapy. Promising signs for therapy have been reported; Nature 361: 486; NS (20 March 1993), 7. The UK national blood replacement service has been promoted as a future vehicle of gene therapy.
In the March meeting of the NIH RAC six clinical gene transfer trials were approved, and four were deferred. The next meeting is in June, and it remains unclear how long a case-by-case approach will continue for; Biotechnology 11: 441. Comments and letters on gene therapy review in the USA are in Science 259: 1391-2, 1678-9; Biotechnology 11: 252; JAMA 269: 843; Lancet 341: 663. The French charity Genethon , which has completed the first physical map of the human genome, is moving to focus on development of gene therapy vectors; Nature 361: 671.
The gene therapy trial for inherited hypercholesterolemia has been a partial success, lowering patient levels of cholesterol; JAMA 269: 837-8. On liver stem cells see Science 259: 1829. A review on the use of gene therapy in cancer treatment is in BMJ 306: 665-6.
An ethical discussion of identity and gene therapy is R. Elliot, "Identity and the ethics of gene therapy", Bioethics 7: 27-40. A book review of D. Heyd, Genethics: The moral issues in the creation of people (Univ. California Press 1992, 276pp., US$45) by P. Singer is in Bioethics 7: 63-7. It also looks into the issues of identity and how to consider future generations' interests in ethical decisions. See also JME 18 (1992), 221.
The possibility of genetically altering brain cells for use in transplantation is strengthened by two resent studies; Nature 362: 414-5; S. Jiao et al., "Long-term correction of rat model of Parkinson's disease by gene therapy", 450-3; p. 453-5. French scientists have announced that adenovirus can be used to transfer genes into rat brain cells; G. Le Gal La Salle et al., "An adenovirus vector for gene transfer into neurons and glia in the brain", Science 259: 988-91;NS (20 Feb 1993), 15. Adenovirus has also been used to transfer a minidystrophin gene to a model of muscular dystrophy with good results; T. Ragot et al., "Efficient adenovirus-mediated transfer of a human minidystrophin gene to skeletal muscle of mdx mice", Nature 361: 647-50.
A genetic targetting approach to attack melanoma cells that have a specific gene defect is discussed in NS (6 Mar), 6. The germ-line transmission of long genes may be possible using yeast artificial chromosomes (YACs), as shown in a mouse study with the collagen genes; Nature 259: 1904-7; and tyrosinase gene in mice, Nature 362: 362: 258-61; also p. 205-6, 255-8. The use of particle bombardment to transfer genes in rat is in Biotechnology 11: 497-502. The use of phosphorodithioate DNA as a therapeutic drug for HIV is reported in Science 259: 1564-70.

In Japan the first gene transfer proposal (for marking bone marrow transplant cells) has been made by Niigata University, however it will still be some time before it is approved. The regulatory situation (see EEIN 3: 38) is that the Ministry of Health and Welfare has issued guidelines for national hospitals, and could review proposals after local committee review; however, all university hospitals are also under regulatory control of the Ministry of Education, which is yet to issue guidelines. A working group is developing guidelines and they could be issued soon. University hospitals would require the permission of both ministries, after local ethics committees approve proposals. The University of Tsukuba has set up a working group to issue University guidelines by March 1994 (D. Macer is one member). It is likely (and hoped) that the two Ministries will coordinate review procedures.
There are animal trials of gene therapy underway in several Japanese laboratories, and a trial for diabetes gene therapy by insertion of a new protein has worked in animal experiments at Tohoku and Kanazawa University; Yomiuri Shinbun (10 May 1993), 1. Gene therapy is getting front page news treatment in some Japanese newspapers, and public acceptance is very high.
The UK has also set up a new gene therapy advisory committee, headed by Dame June Lloyd, centred in the Dept. of Health. Since November 1992 the committee on the ethics of gene therapy (Clothier report), has met 5 times to review applications. Approvals have been given for the treatment of two children with ADA deficiency and one cystic fibrosis gene transfer has also been approved. A number of other proposals are under review (communicated by A.J. Taylor, Committee on the Ethics of Gene Therapy, Wellington House, 133-155 Waterloo Rd, London SE1 8UG, U.K.). A report on a European conference on gene therapy is in Lancet 341: 1339.
A list of ten principles for use by the NIH in special expediated cases of gene therapy is in the HCR 23(3), 3. These guidelines follow criticism of a decision by B. Healy, Director of the NIH, to bypass the NIH committee, and pave the way for future cases in dying patients. On the funding of gene therapy studies in the USA see a letter to Science 260: 877.
A new gene therapy trial in the US for ADA deficiency is being tried by a company CellPro and Children's Hospital Los Angeles; GEN (1 Jun), 28. The ADA genes are transferred into stem cells obtained from umbilical cord blood of newborn infants afflicted with SCID. However this requires prior notice that the children will be infected with the immune deficiency. The gene causing SCID has been identified making gene therapy possible; SA (June 1993), 12. A popular press report of 3 attempts to cure SCID in Californian hospitals in mid-May is in Time (early June 1993); Asahi Shinbun Evening News (24 May 1993), 7.
A popular story of two children who underwent the first gene therapy trials for ADA deficiency, and the success of their therapy, is in Time (7 June 1993), 36-9. A scientific review of gene therapy by R.C. Mulligan is in Science 260: 926-32. There are still important advances in gene delivery and cell transplantation required. A general review of gene therapy, reprinted from an earlier issue of SA is in SA (Medicine), 78-85.
Mice trials of therapy for colon and muscle cancer resulted in clinical trials in 12 patients with skin cancer at the University of Michigan; PNAS 90: 4645-9; NS (22 May 1993), 16. Trials of gene therapy against brain tumours are reviewed in JAMA 269: 2181-7. The direct introduction of genes into tumours in vivo is reported in PNAS 90: 4645-9. Also on gene therapy for cancer, BMJ 306: 1071.
Gene therapy for Parkinson's disease is discussed in NS (24 April 1993), 18; and for cystic fibrosis in Archives of Diseases in Childhood 68: 437-43. An approach for cystic fibrosis therapy in the biliary tract of rats worked; PNAS 90: 4601-5.
The transfer of low density lipoprotein receptor gene by adenovirus accelerates the clearance of cholesterol in mice; PNAS 90: 2812-6 (for a contrasting enzymatic approach in rabbits see PNAS 90: 3476-80). The use of adenovirus for liver targetting is also reported in PNAS 90: 2122-6. The use of herpes simplex virus as a vector for the brain is reported in PNAS 90: 3655-9.
Many AIDS researchers are moving into the area of gene therapy; JAMA 269: 2189-90, 2880-6. Mouse studies have shown that genetic transfer of the HIV protein gene gp160 results in antibody production to HIV-1 which could be a counter to infection, GEN (1 Jun), 32; PNAS (may1). Ways to increase the chemical potential of the germ-line antibody repertoire by introduction of a metal-ion-binding light chain into the mouse genome is reported in PNAS 90: 4008-11.
The use of triple helices for therapy is reviewed in Cell 73: 217-23. The effects of injecting cytokine genes into skeletal muscle in mice shows that this can regulate in vivo immune responses, PNAS 90: 4523-7. On the mechanism of DNA repair see Nature 363: 114-5; and on DNA methylation see Cell 73: 429. The use of a chemical 1,10-phenanthroline-copper linked to RNA to cut double stranded DNA in a sequence specific manner is reviewed in Nature 363: 474-5.
Several papers on religion and gene therapy are; R.-S. Sirat, "Therapie geneque et religions", IJB 4: 5-10 (in French, a Jewish view); J.D. Cassidy & E.D. Pellegrino, "A catholic perspective on human gene therapy", IJB 4: 11-8. The "permissible" limits of gene therapy from catholic church statements are discussed, with six moral principles. They reject any eugenic applications.
A list of 8 companies developing gene therapy technology to the level of clinical trials is in Science 260: 914-5. An overview of gene transfer methods and gene therapy is in GEN (1 Jun), 26-7, 33. A new gene therapy company, GenVec, has been founded in the USA to develop in vivo therapy for cystic fibrosis and other diseases; GEN (15 March 1993), 27. A company NuGene, founded in 1992, is developing ecotropic viruses as vectors; GEN (1 Jun), 8, 32. They are trying to develop therapies against brain tumours.

A review of the 42 review proposals for gene therapy dealt with by the RAC in the USA from N. Wivel, Director of the Office of Recombinant DNA Activities, NIH, is in GEN (15 June 1993), 4. In the June meeting the NIH RAC approved another 11 gene transfers to humans, Biotechnology 11: 780. A law suit against the NIH growth hormone child studies has been filed, Nature 364: 179.
A new journal, Gene Therapy, will be released from Macmillan magazines, from Autumn 1993. Reports from a conference on gene therapy delivery systems are GEN (Aug 1993), 1, 14, 30; Lancet 342: 234. From a conference on gene therapy for Ischemic heart disease, Amer. J. Med. Sciences 306: 129-36. There are many alternatives to retroviruses that have been tested. A meeting report from the UK on progress in gene therapy is TIBTECH 11: 114-7; also in the UK, BMJ 306: 1625-6.
A successful transfer of dystrophin to mice eliminated dystrophic symptoms, suggesting gene therapy for muscular dystrophy in humans will be attempted soon, Nature 364: 673-4, 725-9. Direct gene transfer of DNA in liposomes into the veins of mice can transfect all tissues; Science 261: 209-11. A review of site-specific recombination is FASEB J 7: 760-7. The delivery of antisense into the brain is discussed in Lancet 342 (31 July 1993).

Two trials for gene therapy as AIDS vaccines have been recently approved in the USA; Lancet 342: 799. The use of genes as vaccines is reviewed in PNAS 90: 7427-8; Science 261: 1114. On gene targeting, PNAS 90: 7431-5.
A review is C.A. Stein & Y.-C. Cheng, " Antisense oligonucleotides as therapeutic agents - is the bullet really magical?", Science 261: 1004-11. The use of gene deletion for cancer therapy is explored theoretically in Lancet 342: 662-4, with a number of possible strategies for different cancers mutations. A rat model trial of a therapy for neointimal hyperplasia is reported in PNAS 90: 8474-8. A review of tissue engineering is in Biotechnology & Bioengineering 42: 909-30.
Progress in the treatment of thalassemia is slow, and gene therapy is hoped for, NEJM 329: 877-8. A mouse model is K.R. Peterson et al., "Transgenic mice containing a 248kb yeast artificial chromosome carrying the human b-globin locus display proper developmental control of human globin genes", PNAS 90: 7593-7. A trial in HeLa cells to restore correct splicing is Z. Dominski & R. Kole, "Restoration of correct splicing in thalassemic pre-mRNA by antisense oligonucleotides", PNAS 90: 8673-7. A review on the use of YAC transgenes to transfer large genes is in PNAS 90: 7909-11.
The results of human trials using adenovirus as a gene vector for cystic fibrosis are encouraging, Cell 75: 207-16; Nature 365: 691-2. Trials using adenovirus in mice for recovery from muscular dystrophy are very encouraging, N. Vincent et al., "Long-term correction of mouse dystrophic degeneration by adenovirus-mediated transfer of a minidystrophin gene", Nature Genetics 5: 130-4. Adenovirus can be obtained at high tires after purification, about 100,000 times more. Therefore it is a promising route. The first trials of liposome vectors for clinical trials of gene therapy began in a UK trial for cystic fibrosis recently, Nature 365: 4. The mouse study which suggests it will work is E.M.F.W. Alton et al., "Non-invasive liposome-mediated gene delivery can correct the ion transport defect in cystic fibrosis mutant mice", Nature Genetics 5: 135-42. A number of groups in Germany including company researchers are preparing for more gene therapy trials; Nature 365: 197.

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