Home | Organization | Members | News and Info. | Publications | Products | Interesting Links | library | Secure | Contact Us

Gene therapy

The term gene therapy applies to approaches to disease treatment based upon the transfer of genetic material (DNA, or possibly RNA) into an individual. The concept of gene therapy has been inspired by major discoveries made in basic genetic research since the 1950s, and strategies for gene delivery were matured through the 1980s leading to the first clinical trial in 1990. Today's gene therapy research may be seen as pursuing intelligent drug design through a logical extension of results of fundamental biomedical research on the molecular basis of disease. Since the first clinical trial, a few thousand patients have participated in clinical trials for gene therapy. The most important success of this new type of therapies is presented by the gene therapy trial for X-linked severe combined immune deficiency (conducted by Drs. Marina Cavazzana-Calvo and Alain Fischer from the Hopital Necker Enfants Malades in Paris) resulting in the effective and life-saving immune reconstitution in 10 out of 11 patients, although it revealed also the potential toxicity of this treatment. Despite this success, gene therapy is still in its infancy and a long way has still to be gone in order to offer gene therapy as a regular treatment for any disease. Another very significant advance is the exon skipping approach using viral vectors (see also: vectors for gene delivery). Using such an approach it could be shown in in vivo studies (animal model for Duchenne's muscular dystrophy) that defective dystrophine could be repaired (= expression of a functional but shorter form of the dystrophine molecule)(Goyenvalle et al. (2004) Rescue of Dystrophic Muscle Through U7 snRNA-Mediated Exon Skipping. Science 306, 1796-1799).

Disease targets

While initially focussing on inherited single-gene disorders, gene therapy research is now directed towards a diverse group of human diseases possibly amenable to therapy by gene transfer. Under current investigation at the preclinical or clinical stage are gene therapy strategies for acquired diseases, such as cancer or AIDS, and inherited diseases, such as cystic fibrosis, muscular dystrophy, hemophilia A and B, adenosine deaminase deficiency, severe combined immunodeficiencies, cardiovascular diseases (restenosis, familial hypercholesterolemia, peripheral artery disease), Gaucher disease, alpha1-antitrypsin deficiency, rheumatoid arthritis, high blood pressure, obesity, and others.

Gene therapy strategy

Any gene therapy strategy must be based upon the identification or design of a gene that may aid in the management or correction of a disease. The termination of the Human Genome Project as well as new proteomic and metabolomic approaches will increase the availability of molecular targets and is expected to substantially increase our understanding of genetic but also regulatory components of human diseases, thus aiding the identification of candidate therapeutic targets (i.e. genes). However, to go from the identification of a gene to proposal of a gene therapy strategy requires a detailed knowledge of disease pathophysiology and the biology of relevant target cells.

Vectors for gene delivery

To allow transfer and proper function in a patient the therapeutic gene must be built into a vector. The most efficient gene delivery systems currently available are based upon the gene transfer machinery used in nature by animal viruses. Other gene transfer systems use naked DNA or DNA coupled to chemicals that may facilitate various steps of entry of DNA into cells. In addition, approaches like exon skipping and siRNA (small interfering RNA) are very promising. By the ex vivo gene transfer principle genetic material is transferred to cells outside the host; following transfer the genetically modified cells are then implanted into the host. By the in vivo gene transfer principle, genetic material is transferred directly to cells located within the host. However, major challenges remain with respect to both types of gene delivery strategies in terms of efficient gene transfer to the desired cell types and proper control of expression of the inserted gene. Moreover, problems of this nature mostly need to be addressed specifically for each individual disease or target cell.

Interference with immune system

Other major issues of current gene therapy research concern the reaction of the immune system of the treated individual. While some gene therapy strategies, such as cancer immunotherapy, attempt to stimulate the reactivity of the individual's immune system towards eliminating the cancer cells, other strategies require that the genetically modified cells be protected from destruction by the immune system, signifying that a functional and well developed gene therapy approach for gene repair or the expression of correct/corrected proteins in patients with inherited disease associated with a missing or a truncated form of a protein will obligatorily be associated with a sophisticated manipulation of the immune system (e.g. induction of immune tolerance). Only in the cases of the different forms of SCID, the activation of the immune response is no problem because the patients are devoid of a functional immune system.

Clinical trials in gene therapy

Between 1989 and 2003, 790 gene therapy clinical trials have been worldwide approved. At the end of January 2004, there have been (worldwide) approximately (source: http://www.wiley.uk.co/genmed): * More than 3,500 patients that received gene therapy treatment; * 907 gene therapy protocols, of which 608 addressed cancer, 90 for monogenic diseases, 76 for vascular diseases, 60 for infectious diseases (predominantly AIDS) and 53 for gene marking studies, 7 protocols involved healthy volunteers The vectors used were: retroviral vectors (in 254 protocols) adenoviral vectors (in 240 protocols) naked/plasmid DNA (132 protocols) lipofection (in 85 protocols) pox virus vectors (52 protocols) Vaccinia virus vectors (30 protocols) Herpes simplex virus (26 protocols) AAV (adeno-associated virus) (19 protocols) variety of other (69 protocols) The gene types transferred were the following: Cytokine (237 protocols) Antigen (128 protocols) Tumor suppressor (113 protocols) Suicide gene (74 protocols) Deficiency (68 protocols) Drug resistance (56 protocols) Receptor (31 protocols) Replication inhibitor (27 protocols) Others (173 protocols)   The clinical phases addressed were (protocols/phase): phase I (In Phase I clinical trials, researchers test a new drug or treatment in a small group of people (20-80) for the first time to evaluate its safety, determine a safe dosage range, and identify side effects): 64% phase I/II: 22% phase II, (In Phase II clinical trials, the study drug or treatment is given to a larger group of people (100-300) to see if it is effective and to further evaluate its safety): 13% phase II/III: 1% phase III (In Phase III studies, the study drug or treatment is given to large groups of people (1,000-3,000) to confirm its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow the drug or treatment to be used safely): 1.6 % Remark: For clinical trials of rare diseases, the number of patients per phase is considerably reduced, for instance, for a phase I clinical trial of a rare disease 5 to 10 patients are enrolled. The result of all these protocols has been that a solid database of clinical experience has been built and that clinical research has moved away from the proof of concept stage. The very successful gene therapy trial for X-linked severe combined immune deficiency (conducted by Drs. Marina Cavazzana-Calvo and Alain Fischer from the Hopital Necker Enfants Malades in Paris) resulted in the effective and life-saving immune reconstitution in 10 out of 11 patients. These patients have been able to lead a normal life, indicating, that from a clinical point of view they should be considered as cured. However, very sadly, three of the treated patients came down with a T-cell lymphoproliferative disorder and it could be established for two of these cases that the retroviral vector was found integrated in the proximity of the LMO-2 gene in the proliferatingve T-cells (more informations can be found on the web site of ESGT: www.esgt.org: SCID Gene Therapy in France on Clinical Hold Due to Diagnosis of a Third Case of Lymphoproliferative Disorder). Subsequently the patients have been treated by chemotherapy. One of the children who had developed leukaemia had succumbed to the leukaemia. This adverse effect led to a considerable rethinking on the safety issues of viral vectors used for gene therapy purposes. However, it is also evident that more pre-clinical investigations in assessing the risk of gene therapy, including more basic research in the development of safer gene transfer vectors will be needed. Despite this adverse event, both, the public attitude towards gene therapy and international regulatory requirements have evolved. In addition, hurdles to clinical success have been identified, indicating which basic issues still need to be resolved and how to start an iterative process between the laboratory and the clinic.

ACTIP and gene therapy

While major problems need to be solved for gene therapy to become a standard way of treating people, the field continues to attract strong attention from researchers, clinicians and industry. Gene therapy and the production of gene therapy products use molecular and cell biological methods similar to those used for in vitro cultivation of cells in the manufacture of biologicals. It therefore seems logical that ACTIP monitors developments in gene therapy technology and applies its expertise on issues such as regulatory requirements, guidelines and public perception. Otto-Wilhelm Merten, Crespières, 29.12.05

Back To Top. | Home | Organization | Members | News and Info. | Publications | Products | Interesting Links | library | Secure | Contact Us © 2006 ACTIP