Gene Therapy OLD News
Extracts from EEIN 1991-1994. Latest news is at the bottom. Provided by Eubios Ethics Institute , at http://eubios.info/index.html.
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Abbreviations for journals
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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