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Results

• Focus on the results in 2007
• Focus 2006
• Major breakthroughs achieved
• Focus on the exon skipping

• In 2000, Pr Alain Fischer and Dr Marina Cavazanna-Calvo (Inserm, Hôpital Necker-Enfants Malades) announced that several babies suffering from severe immunodeficiency syndrome were able to leave their protective sterile bubble and start leading a normal life as a result of a gene therapy. In 2002 a complication occurred in two of the eleven children treated. As a precaution, the trial was interrupted to enable scientists to understand what had happened, with a view to improving future gene therapy strategies. On 9 June 2004 the French Health Products Safety Agency (AFSSAPS) announced the resumption of the trial – scientific research into the complication showed that the risks vs benefits of the therapy remained globally positive.
  On 24 January 2005 AFSSAPS signalled a third case of complication. Pending the results of an analysis of this, the French health authorities decided to suspend the trial.
  As in the two previous cases, the third consisted of an uncontrolled proliferation of T-lymphocytes. Investigations are under way to identify the origin of this proliferation and define if the insertion of the retroviral vector in the genome as in question, as in the first two cases (see the AFM press release of 17/10/2003).
  However, the AFM believes that this new complication only confirms that more work must be done in order to:
  - improve the vectors used
  - develop new, more efficient vectors such as the lentivirus which are on offer today for transporting gene-drugs in hematopoietic stem cells
  - better understand and control the immune system
  - develop new gene therapy techniques such as exon skipping
  - set up trials in humans which 
  - in safety conditions regulated by health authorities – enable upcoming problems to be identified and solved.
  Also, in 2002 an Italian-Israeli team were again successful in treating two children affected with immune deficiency. The AFM played a part in this work by supporting the Italian team involved in the trial.
   
• Another breakthrough includes a first feasibility trial for neuromuscular diseases. The first gene therapy trial in Duchenne and Becker muscular dystrophies which started in 2000 at the Myology Institute in Paris was completed in 2002. Although no direct benefits are expected, this trial sets an example for the development of protocols and respect of patients’ safety.
  Presented during the Annual Meeting of the American Society of Gene Therapy in 2003, the results of this trial conducted in collaboration with the Transgène biotech, demonstrated for the first time the feasability of this technique. They showed that it is possible to obtain a local expression of dystrophin with no immune reactions, in patients affected by Duchenne or Becker muscular dystrophies.
  Precisely :
  -Presence of plasmid-dystrophin in all the patients
  -Expression of dystrophin in low quantities in 6 patients
  -Excellent clinical tolerance after plasmid administration.
  This trial must be continued in order to increase the protein expression level and to extend the targeted muscle territories.
  
  
• Finally, in the field of cell-based therapies, the results of studies supported by AFM were published in 2000 and 2001. Patients affected by Huntington’s disease, a severe neurodegenerative disease, show an improvement of their intellectual and motor functions after a cell therapy. Moreover, muscle cell transplantation improved heart function after a myocardial infarction.
  
  
• In 2005 results were obtained in humans :
  - demonstration of the preventive effect of perindopril on heart failure in Duchenne muscular dystrophy
  - BONAMI clinical trial : cardiac cell therapy trial using hematopoietic stem cells on coronary thrombosis. 47 patients have been included so far (23 treated and 24 controls) out of the 100 planned.

• The flagship result for the year 2006 concerns a team of Italian researchers led by Michele De Luca. Financed by the French and Italian Téléthons, the team has succeeded in treating the skin surface of a patient affected with a severe genetic disease, junctional epidermolysis bullosa by the transplant of epidermic cells treated by gene therapy.
  Blind dogs have had their vision restored by gene therapy and the muscles of diseased mice have been repaired with gene surgery.
  In humans, 17 bubble-babies in France and England have had their immune systems restored by gene therapy. And in Italy 8 children affected with immune deficiency are now leading a normal life thanks to gene therapy under the leadership of Maria Grazia Roncarolo (TIGET, financed by the French and Italian Téléthons).
  One team has demonstrated the feasibility and effectiveness of a gene therapy by gene transfer in a canine model of Hurler disease, and a group of French and Italian researchers has show the effectiveness of cell therapy in dog models of Duchenne muscular dystrophy.

• Among the results announced in 2000, Pr Peschanscki’s (Inserm, Hôpital Henri Mondor, Créteil) research work on Huntington’s disease continued in 2002 with a new phase II clinical trial. This trial will include 100 patients at six centers in Belgium, England, Switzerland and Italy. The objective of this trial is two-fold : to extend the results obtained for a few patients to a greater number of patients, but also to train a greater number of specialists for this type of operation.
• Similarly, the results obtained for two immune deficiencies (ADA and SCID-X) have opened the way to research work on gene therapy for other immunodeficiencies. A collaboration has thus started between Pr Fischer who led the first trials, and Genethon, AFM’s gene therapy research and applications center which develops vectors used in the trials, conducts preclinical studies and draws up clinical protocols. These trials are carried out in collaboration with Italian teams.
• On the other hand, after the first conclusive experimental results, AFM decided not to continue its participation in the cell therapy trials for myocardial infarction. Genzyme pursues, on a larger scale, research work for this common disease.