PARIS -- Transgène SA said it hopes to embark on the first clinical trial in humans of a gene therapy for two forms of muscular dystrophy -- Becker's dystrophy and Duchenne's disease -- in the second half of 1999. The trials will be largely financed by the French Muscular Dystrophy Association (AFM), with which Transgène signed a second cooperation agreement on Nov. 30.
Under the new accord -- which runs to June 30, 2001, and renews the original three-year convention the two organizations signed in July 1995 -- the AFM is to provide funding of FFr84 million (US$14.7 million) to Transgène's gene therapy research program, including FFr20 million in the form of an interest-free loan that will be repayable in the event a product arising from this collaboration reaches the market.
The Phase I trial will take place at the Institute of Myology, located in La Pitié-Salpétrière hospital in Paris and jointly financed by the AFM and the Paris public hospital authority. The trial will test the tolerance and efficacy in humans of a therapy for muscular dystrophy that was developed on mouse models and has been shown to work in dogs, explained Bernard Gilly, managing director of Transgène. "We have succeeded in transferring modified genes into a significant number of cells in the muscles of dogs . . . and this trial will try to obtain answers to a number of questions about using this kind of therapy in man," he said.
The trial protocol, which has been submitted for the approval of France's Medicines Agency, entails the local injection of naked DNA (in this case a plasmid) into a limited area of muscle in patients suffering from one or other form of muscular dystrophy. The aim is to establish that the introduction of this DNA into human muscle tissue will lead to the production of dystrophin (the protein that is missing in muscular dystrophy sufferers), and that the dystrophin remains on the inside face of the cell. The trial will not be designed to demonstrate a therapeutic effect, but investigators will be watching to see if the production of this protein triggers any immune responses.
In addition, the trial will enable Transgène to determine which of its vectors is most suited for this type of gene therapy. "Transgène considers that the diversified platform of vectors it is developing could enable it to select a reliable and effective vector for inserting genes into muscles," said Gilly. The Strasbourg-based gene therapy company has developed five vectors for gene delivery, three of which are in clinical development for the treatment of various cancers and cystic fibrosis.
The signing of the agreement with Transgène coincided with the launch by the AFM of what it describes as its "Great Endeavor," a five-year program for encouraging the development of gene therapy techniques in which it plans to invest more than FFr1 billion. To that end, it has established an international network of clinics and research establishments in Europe and the U.S. working on different aspects of gene transfer technology and committed to sharing and exchanging the results of their research. In France, for instance, the AFM is providing funding not only to Transgène but also to La Pitié-Salpétrière hospital, which has created an in-house integrated gene therapy center. In 1999 it expects to finalize an agreement with the Institut Gustave Roussy, of Villejuif, near Paris, Europe's largest cancer center, covering the production of gene transfer vectors and the conduct of clinical trials of gene therapies for rare genetic diseases.
Also in France, the AFM has established a national vectorology network which encompasses Généthon, based at the Génopôle in Evry, south of Paris, a laboratory specialized in the production of both research and clinical-grade vectors, and the gene therapy units of Nantes general hospital in western France and the Institut Paoli-Calmettes cancer clinic in Marseille. Généthon is almost entirely funded by the AFM, which is providing it with FFr403 million over five years (from 1998 to 2002), while the other units are receiving annual funding from the AFM of FFr3.7 million and FFr3.5 million, respectively, over three years. In addition to its funding for Généthon, the AFM is providing a further FFr64 million over five years to finance a laboratory in Boston that Généthon has set up in conjunction with Harvard Medical School for the research, development and production of vectors.
The AFM obtains all its funds from private donations, mainly by means of an annual television special called the Telethon, the 12th edition of which raised a record FFr450 million. *