The Gene Therapy Advisory Committee (GTAC).
In 1992, the Clothier Committee issued its report on the Ethics of Gene Therapy, which recommended that gene therapy (or gene transfer) in humans should be restricted to life threatening diseases or disorders. To oversee and implement this, GTAC, a non-statutory body, was established in 1993. GTAC advises on the ethical acceptability of proposals for gene therapy research on humans taking account of the scientific merits and the potential benefits and risks, and provides advice to UK Health Ministers on developments in gene therapy research. A primary concern of GTAC is whether each research proposal meets accepted ethical criteria for research on human subjects. This includes both therapeutic and non-therapeutic research. GTAC approval must be obtained before gene therapy research is conducted on human subjects

The Workshop.
Whilst there has been a significant increase in the number of gene therapy clinical trials conducted in the UK in the past few years, the vast majority of research has been aimed at cancer treatment. However, more recently, a number of high profile reports have indicated that gene therapy can be effective in treating some of the inherited monogenic disorders, such as Haemophilia-B or X-linked Severe Combined Immunodeficiency.

The "Gene Therapy for Inherited Disorders" workshop was designed to examine these latest advances in the treatment of genetic disease, to discuss possible future directions in gene therapy research and encourage dialogue and debate amongst all interested parties: from scientists and clinicians to ethicists and patient groups. As well as presentations from invited speakers, attendees participated in focussed discussion groups to examine specific issues in current gene therapy research. Summaries are provided below.

Biographies of the Speakers:

Professor Norman Nevin:
Norman C. Nevin is Professor of Medical Genetics, Queen's University of Belfast and Head of the Northern Regional Genetics Service. He has held the positions of secretary, vice-president and president of the UK Clinical Genetics Society as well as serving on various national and international committees notably the Human Genetics Advisory Commission. He is a member of the European Concerted Action for congenital abnormalities. Professor Nevin was a founder member of the UK Gene Therapy Advisory Committee (GTAC) and is currently its' chairman. His research interests have resulted in over 300 peer reviewed publications on various aspects of genetics, especially single gene disorders and congenital abnormalities.

Dr. Katherine High:
Katherine High graduated from Harvard with a degree in Chemistry before carrying out her M.D. studies at the University of North Carolina (UNC) School of Medicine. She then trained as a Fellow in the Hematology Section at Yale University School of Medicine for four years, before returning to UNC as a faculty member in the Department of Medicine and the Curriculum in Genetics. Later, she moved to Philadelphia to her present concurrent positions as director of the Research in Hematology at The Children's Hospital and William H. Bennett Professor of Pediatrics and Pathology at the University of Pennsylvania.

Her research interests have focused on molecular genetic basis of and development of novel therapeutics for haemophilia. She has published numerous scientific articles, including one of the first reports that gene therapy could be used to successfully correct an inherited disorder. She is an active member of the American Society of Hematology, the National Hemophilia Foundation and the Program Committee on Genetic Diseases of the American Society of Gene Therapy. She has also served on the editorial boards of the American Journal of Hematology, Human Gene Therapy and Molecular Therapy.

Dr. Alain Fischer:
Alain Fischer received his MD and PhD degrees before training as a postdoctoral researcher at University College London with Professors Beverley and Feldmann on human antigen specific T cell clones. He later became Professor of Pediatric Immunology at Necker Hospital in Paris and is now Head of the Pediatric Immunology and Haematology Clinical Unit. He also heads the INSERM Research Unit «Normal and Pathological Development of the Immune System». His research interests include primary immunodeficiencies, genetics of immunological disorders and gene therapy.

He has served as President of the Immunology Committee at INSERM, currently is a gene therapy adviser and member of the scientific committee of Association Française contre les Myopathies and an adviser for medical research at the Ministry of Research. He is also president of the scientific committee of Fondation de la Recherche Medicale. He has received awards from the NRJ Fondation-Institut de France and the Pierre Royer Prize. His recent publication in Science on effective gene therapy for X-SCID has been received as a seminal breakthrough in the field (Cavazzana-Calvo et al., 2000)

Dr. Deborah Gill:
Deborah Gill is a member of the recently-formed UK Consortium for Cystic Fibrosis Gene Therapy and works in the Nuffield Department of Clinical Laboratory Sciences at the University of Oxford, developing a gene therapy for Cystic Fibrosis lung disease.

Deborah has a Ph.D. from Warwick University where she was involved in the initial discovery of the ABC (ATP-Binding Cassette) super-family of membrane proteins. Following post-doctoral work she moved in 1990 to the Institute of Molecular Medicine in Oxford to work on two human members of the super-family, the multi-drug resistant P-glycoprotein and the CFTR protein responsible for Cystic Fibrosis. Since 1993 Deborah has designed, instigated and published the results of two clinical trials of gene therapy for cystic fibrosis.

Ian Muchamore:
Ian Muchamore is Senior Project Manager for Consultation and Research in the Medicine in Society Programme at the Wellcome Trust. He was trained as a geneticist and developmental biologist before moving into the Public Understanding of Science area where he has been active for the last eight years. In that time he has developed educational initiatives including exhibitions, a hands-on DNA based workshops for schools and a theatre in education play which encourage students to discuss the social and ethical issues raised by genetic testing. He has organised many public debates and policy discussions. This work has been underpinned by the commissioning of rigorous social research to explore public opinion and attitudes. Previous studies have explored wider public perceptions of human cloning and stem cell technologies, embryo screening and prenatal testing, and gene therapy in different contexts.

PRESENTATION ABSTRACTS:

KEYNOTE PRESENTATION: Trials & Tribulations
Professor Norman C Nevin, GTAC Chairman.

Several thousand single gene disorders have been described; most of them are rare. Many result in serious illness and where there are conventional treatments these may be inadequate or burdensome. The prospect of somatic gene therapy (providing working copies of defective genes in those cells which need it for their proper function) is attractive if it can cure or alleviate disorders that impact so greatly on the patients' lives.

Although gene therapy emerged as a potential treatment for genetic disorders, in practice the majority of protocols world-wide have aimed to harness its' potential for the treatment of cancer. As we reach the end of this first decade of gene therapy research, encouraging evidence of positive clinical results have emerged from trials and there has been a resurgence of interest in applying gene therapy approaches to treatments for inherited disorders.

This presentation will look back at the brief history of gene therapy research and examine some of the many and varied approaches that have been developed to improve gene delivery, gene targeting and patient safety. It will also look to the future and ask whether gene therapy is showing signs that it may fulfil its enormous potential.

In order to fulfil that potential gene therapy clinical trials must continue to be conducted to the highest scientific and ethical standards with patient welfare and safety being paramount. The Gene Therapy Advisory Committee (GTAC) is the UK advisory body, established by Government and charged with the oversight of the conduct of gene therapy. The work of the Committee, including its remit, mode of working and recent important initiatives will be discussed in the context of current developments in human gene therapy.

AAV-mediated gene transfer for hemophilia B.
Mark Kay, Roland Herzog, Valder Arruda, Catherine Manno, Amy Chew, Linda Couto, Alan McClelland, Bertil Glader, Katherine High

We have been working to establish an experimental basis for a gene transfer approach to treating hemophilia. Using an adeno-associated viral vector (AAV) expressing Factor IX introduced into skeletal muscle, we have shown in mice and in hemophilic dogs that we can achieve long-term (>3 years) expression of clotting factor at levels that would result in an improvement in clinical symptoms of the disease. A phase I trial of intramuscular injection of AAV-F.IX has been initiated to evaluate the safety of this procedure in patients with severe hemophilia. To date, eight subjects have been enrolled at three doses, ranging from 2 x 1011 vector genomes/kilogram (vg/kg) to 2 x 1012 vg/kg. There has been no evidence of local or systemic toxicity in any of the subjects, including no evidence for inhibitor formation or for inadvertent germline transmission of vector sequences. Muscle biopsies have shown unequivocal evidence of gene transfer and expression by PCR, Southern blot, and immunohistochemistry. Some subjects have shown evidence of circulating F.IX levels above baseline, >1% but <2%, and have had concomitant decreases in clotting factor usage. In additional pre-clinical studies, administration of an AAV vector into the portal vein of hemophilic dogs has resulted in considerably higher circulating levels of F.IX, on the order of 5-14%, whereas delivery to skeletal muscle never resulted in levels higher than 1-2% in hemophilic dogs. A proposed clinical trial of AAV-mediated, liver-directed gene transfer for hemophilia B is now in the late planning stages. We conclude that AAV-mediated gene transfer is a promising approach to the treatment of hemophilia B.

Gene Therapy of Severe Combined Immunodeficiencies.
Alain FISCHER

Gene Therapy represents an attractive strategy for a number of life threatening disorders. Severe inherited immunodeficiencies are among the best possible as (i) available treatments are partially unsatisfactory, (ii) disease related genes are known (iii) gene product expression is likely to provide a growth advantage to corrected cells and (iv) once differentiated, T lymphocytes (the missing cell in these disorders) are long lived. By using defective retroviral vectors, relatively high efficiency gene transfer into hematopoietic progenitor can safely be achieved ex vivo, in the presence of cytokines such as flt-3L, SCF, MGDF and of a fibronectin fragment. Following in vitro and ex vivo (murine model) preclinical studies, we have set up a clinical trial for the X-linked form of severe combined immunodeficiency (SCID) caused by mutations of the yc gene. Five patients were enrolled. Selected CD34(+) cells from patients' marrow were ex vivo infected then re-infused. No adverse effects occurred with a follow-up of almost 2 years. In four patients, a complete correction of T cell immunodeficiency was achieved which is so far sustained. Patients can therefore live normally without any form of treatment. These results provide a proof of principle for the efficacy of gene therapy based on the selective advantage provided to transduced cells. Assessment of long-term results will be required in order to know for how long the effect will persist. Extension of this form of treatment for closely related inherited disorders of the immune system can nevertheless be envisaged.

Gene Therapy for Cystic Fibrosis.
Deborah Gill

Cystic fibrosis (CF) is one of the most common, serious genetic diseases in the UK. Gene therapy is being considered as a possible treatment for CF lung disease, which is the major cause of mortality in CF individuals. We have focused on a non-viral gene transfer vector in which plasmid DNA is complexed with cationic liposomes. Two double-blinded clinical studies, each involving 12 CF patients, in which a gene transfer formulation was administered to the nasal epithelium have been completed by our group. These studies aimed to test the safety and efficacy of single (Gill et al., 1997) and multiple doses (Hyde et al., 2000). The results showed no evidence of inflammation, toxicity or an immune response towards the DNA/liposomes or the CF protein. Nasal epithelial cells were collected after each of three doses for a series of efficacy assays to measure vector DNA and mRNA, CFTR protein, bacterial adherence, and halide efflux ex vivo. Airway ion transport was also assessed in vivo throughout the studies. In the first single-dose study, gene transfer was detected in six of the eight treated patients, although the gene transfer was modest and transient, indicating that repeated administration is likely to be required for long-term gene expression. In the second, repeat-dose study patients were required to attend the out-patient clinic on more than 20 occasions throughout the 4 month study period. The results showed that DNA/liposomes could be successfully re-administered to the nasal epithelium without apparent loss of efficacy. In conclusion, these studies and many others have demonstrated proof of principle for CF gene therapy. Current research is now focused on improving the efficiency and duration of CF gene transfer in the lung.

Gene Therapy: Building a Public Dialogue
Ian Muchamore

The Gene Therapy Consultative Panel was funded by the Wellcome Trust and was a collaboration between the Trust and the National Centre for Social Research. The research followed the knowledge and attitudes of a randomly selected sample of the British public over a one year period. Public attitudes towards gene therapy are more complex than previous research has been able to explore. Public optimism is very high about progress in gene therapy research and many people assume the technology is already in use. More people say they are hopeful about discoveries into human genes than say they are worried about them, although their list of worries is longer and more wide-ranging than their hopes. People make important distinctions between medical and non-medical applications, and between somatic, germ-line and in utero gene therapy. Initially there is widespread support for somatic gene therapy for single gene disorders such as cystic fibrosis with only a slightly lower level of support for a germ-line approach. Opportunities to learn more about the science, hear different arguments and discuss the issues in small groups lead some members of the public to reassess their initial views. Whilst the level of support for single gene therapies was solid during these interventions attitudes towards treating other conditions fell in some cases.

DISCUSSION GROUPS:

Discussion Group 1:
Consent, privacy and confidentiality of patients in Gene Therapy Research

This group discussed issues surrounding patient consent and privacy in gene therapy trials. In particular, it was felt that it would be useful if there was an independently mediated consent procedure for patient enrolment. It would be helpful if there could be a person not involved in the clinical trial or treatment, who could be available for patient advice.

Secondly, the issues of conflicts of interest amongst investigators were discussed. In many cases, the lead researcher may be the practicioner directly responsible for the care of the family involved. In cases where the research was being conducted at a large centre which was being fed from other local centres, it was considered beneficial if consent could first be taken at the local hospital with the primary doctor and then more formal consent taken at the secondary centre.

It was noted that it is now mandatory in the US for an observer to be present while patient consent being taken. It was also noted that there has recently been an increased transparency and openness around the consent procedure in the UK. While there was no wish to hamper research into rare diseases in gene therapy trials, at the same time the participants needed some protection and reassurance. It was suggested that the Wellcome Trust and other organisations would be examining such issues in the future.

Finally, the patient flagging study of GTAC was discussed. There appeared not to be much concern over issues of privacy and confidentiality for participating patients. However, some concern was voiced over the issue of flagging of patients' children up to the age of 16 years. It was suggested that re-consent may be required when examining the records of these children. On the broader issue of family involvement in consent, it was felt that in some cases, family participation and counselling may be advantageous in cases where gene therapy may have health implications for other family members.

Discussion Group 2:
Gene Therapy for Single Gene disorders

This group commented on the fact that when GTAC first came into existence it was envisaged that the majority of research would involve single gene disorders. However, the vast majority of clinical trials using gene therapy involve cancer research. This seems largely to be an issue of funding. While gene therapy for cancers have a clear commercial value, financial returns on single gene disorders may be perceived as potentially low.

A second reason for the lack of gene therapy research into single gene disorders lies in the nature of funding for understanding the basic biology of disease. Again it was felt that funding was inadequate for research into the understanding of basic mechanisms underlying single gene disorders. In addition, whilst treatments for cancers had potentially multiple therapeutic targets, single gene disorders were more likely to yield to one form of gene therapy that will work for that particular disorder based on its biology. This has rendered single gene disorders less attractive targets for funding from industry. Given the recent successes of gene therapy research on single gene disorders, it was felt that this area of research would most likely benefit from public funding. It was also believed that such funding would have a significant potential impact on understanding and treatment of single gene disorders. In summary, there was a feeling that single gene disorders were getting a "raw deal" in terms of research.

The group suggested that as GTAC also had a role in advising ministers, it should advise ministers of the need for public funding into research on single gene disorders. There was a clear funding gap which needed to be filled.

Another issue raised was the fact that because of the rarity of many of the single gene disorders, there may be a problem in getting the number of participants required in clinical trials. It was suggested that this could be achieved via pan-European collaborations.

Finally, the ethical issues of gene therapy research were brought up. It was suggested that GTAC was stringent on safety issues surrounding techniques that were just being transferred from one disease to another. However, it was acknowledged that GTACs primary concern was with patient safety. Another ethical issue raised was the value of animal models and the choice of patient groups. In many cases animal models were unsuitable and normally human subjects that are at the "end-stage" or the disease were involved in trials. In order to prove efficacy there is perhaps a case for carrying out research in patients not so severely affected by their disease, perhaps before tissue damage has occurred. This lead the group to propose that another function of GTAC should be to promote the consideration of techniques such as in utero gene therapy. The group felt that in this case more research needed to be invested into delivery systems.

Discussion Group 3:
Issues surrounding Gene Therapy In utero

Surprise was expressed by this group with the results from the Wellcome study presented by Ian Muchamore, which indicated that the public showed less approval for in utero gene therapy than for germ-line gene therapy. Why did this get a lower rating than germ-line therapy? It was felt that such concern was based upon the fact that in utero therapy would involve direct manipulation of a foetus and consequently envisaged to lead to significant danger to the unborn child. It was suggested that risks associated with germ-line gene therapy were more abstract, less tangible and appeared therefore less egregious than in utero therapy.

This group also recognised that an important issue associated with this form of gene therapy was prenatal screening. Where in utero gene therapy was an option, parents would be faced with the treatment or abortion. At present, there was a considerable amount of counselling available for parents in this situation. Exhaustive prenatal screening for genetic disorders was considered to be prohibitively expensive.

The main ethical question in this discussion related to the efficacy of such treatment. It was suggested that the metabolic diseases would be suitable targets, especially involving the liver, which was considered an easily accessible target. Other disorders open to such intervention would be neurological diseases, which could be treated before brain damage would occur. In general, it was felt that amenable diseases would have to be subject to early diagnosis, should be early onset and most importantly treatment would have to be more effective in utero than immediately after birth.

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