Evry (France), January 12, 2012 - The results of a Phase I clinical trial of
gene therapy for limb-girdle muscular dystrophy type 2C (a rare
neuromuscular disease) have just been published in the journal Brain on
January 11, 2012. The trial started in December 2006 and has been sponsored
by Généthon (the not-for-profit research lab created by the French Muscular
Dystrophy Association (AFM) and which is funded almost exclusively by
donations from France's annual Telethon). The trial at Pitié-Salpêtriere (AP-HP) is
being led by principal investigators Professor Serge Herson (Head of the
Department of Internal Medicine 1) and Professor Olivier Benveniste (Institute of
Myology). The study's primary objective was to evaluate the safety of local
injection of increasing doses of an adeno-associated virus (AAV) vector harboring
a "healthy" copy of the gene for gamma-sarcoglycan (the defective protein in
this disease). Secondary objectives included the assessment of local and
systemic immune reactions and the quality of gene transfer in the injected
muscles in terms of efficacy, expression and distribution.
Nine non-ambulatory patients (aged from 16 to 38) were included in the trial
between December 2006 and December 2009. Three increasing doses of an
AAV1 vector bearing the normal gamma-sarcoglycan gene were injected into a
forearm muscle. One month after the injection, a biopsy was taken from the
treated zone and analyzed.
The trial's results have just been published and are encouraging. Above all, the
injections were well tolerated and not associated with adverse physical or
biological effects. Furthermore, assays in five patients revealed the presence of
RNA produced from the therapeutic gene (RNA is the intermediate genetic
material between the gene and the protein). Immunohistochemical analysis of
injected-muscle biopsy specimens showed ?SGC expression in three out the
three patients who received the highest dose. Furthermore, in one of these
patients (who had received the highest dose of treatment), a western blot assay
revealed that normal protein gamma-sarcoglycan was being expressed in the
muscle fibers. Thanks to gene therapy, the missing gamma-sarcoglycan protein
was being produced anew. Professor Serge Herson commented that "the results
of this trial exceed our expectations. In addition to confirming the treatment's
lack of toxicity (the study's primary objective), we were able to make progress in
other areas, such as trial logistics, immunological aspects and even the optimal dose for treating a set of muscles efficaciously. This result is especially interesting because it means that we have established the dose threshold above
which the treatment becomes efficacious. That’s very rare in a Phase I trial".
The physicians and researchers at Généthon, the Institute of Myology and Pitié-
Salpêtriere (AP-HP) are continuing their work. They intend to set up a new trial
in which an AAV8 vector will be used to treat a whole limb.
Limb-girdle muscular dystrophy type 2C (LGMD2C) is due to a lack of gamma-
sarcoglycan protein. In muscle cells, the sarcoglycans form a complex that
contributes to the stability and mechanical resistance of the cell membrane
during muscle contraction. The lack of a single type of sarcoglycan often leads to
disappearance of the whole complex. The membrane becomes more fragile as a
result, leading to degeneration of the muscle fiber itself.
LGMD2C is clinically characterized by progressive weakness that mainly affects
the limb-girdle muscles. Hypertrophy of the calf muscles and macroglossia (an
enlarged tongue) are frequently observed. The first symptoms appear at 3-5
years of age in the most severe forms and at 10-40 years of age in the mildest
forms. Populations in the Mediterranean basin (northern Africa) and gypsies
living in Europe are particularly affected. At present, there is no curative
treatment for this muscular dystrophy.
For more information:
Source: A phase I trial of adeno-associated virus serotype 1–gamma-
sarcoglycan gene therapy for limb girdle muscular dystrophy type 2C - Brain
2012; doi: 10.1093/brain/awr342, published on January 11, 2012 and available
on this link:
http://brain.oxfordjournals.org/cgi/reprint/awr342?ijkey=jz7sxUCEa0w0jpv&
keytype=ref
Serge Herson 1, Faycal Hentati 2, Aude Rigolet 1, Anthony Behin 3, Norma B Romero 3, France
Leturcq 4, Pascal Laforêt 3, Thierry Maisonobe 3, Rim Amouri 2, Hafedh Haddad 5, Muriel Audit 6,
Marie Montus 5, Carole Masurier 5, Bernard Gjata 5, Christophe Georger 5, Mustapha Cheraï 7,
Pierre Carlier 3, Jean-Yves Hogrel 3, Ariane Herson 3, Yves Allenbach 1, François M Lemoine 7,
David Klatzmann 7, H Lee Sweeney 8, Richard C. Mulligan 9, Bruno Eymard 3, Didier Caizergues 5,
Thomas Voit 3, Olivier Benveniste 1.
1 Université Pierre et Marie Curie, Assistance Publique-Hôpitaux de Paris, Hôpital Pitié-Salpêtrière,
Médecine Interne 1, Paris, 75013, France
2 Department of Molecular Neurobiology and Neuropathology, National Institute of Neurology, La
Rabta, Tunis, 1007, Tunisia
3 Université Pierre et Marie Curie, Assistance Publique-Hôpitaux de Paris, Hôpital Pitié-Salpêtrière,
Institut de Myology, Paris, 75013, France
4 Assistance Publique-Hôpitaux de Paris, Hôpital Cochin, Laboratoire Biochimie Génétique, Paris,
75014, France
5 Généthon, Evry, 91000, France
6 Genosafe, Evry, 91000, France
7 Université Pierre et Marie Curie, Assistance Publique-Hôpitaux de Paris, Hôpital Pitié-Salpêtrière,
CNRS UMR 7211, Paris, 75013, France
8 Department of Physiology, School of Medicine, University of Pennsylvania, Philadelphia,
Pennsylvania, 19104, USA
9 Harvard Gene Therapy Initiative, Department of Genetics, Harvard Medical School, Boston,
02115, USA
About the AFM
The French Muscular Dystrophy Association (AFM) federates patients with neuromuscular diseases
(genetic diseases that kill, muscle after muscle) and their parents. Thanks in great part to
donations from France's annual Telethon (€90 million in 2010), the AFM has become a major player
in biomedical research into rare diseases in France and worldwide. It is currently funding 36 clinical
trials on 31 different genetic diseases affecting the eyes, the blood, the brain, the immune system,
the muscle... Thanks to its Généthon research lab, the AFM stands out through its unique ability to
produce and test its own gene-based medicines.
More information at www.afm-telethon.fr
About Généthon
Created by the French Muscular Dystrophy Association (AFM), Généthon is funded almost
exclusively by donations from France's annual Telethon. Its goal is to deliver innovative gene
therapies to patients. After having played a pioneering role in deciphering the human genome, with
over 200 scientists, physicians, engineers and regulatory affairs specialists, Généthon is one of the
world's leading centers for preclinical and clinical research and development in the field of gene
therapy for rare diseases. Généthon also has a biomanufacturing platform for clinical-grade
vectors, that will open in Evry in 2012, the world's largest facility for pre-industrial pilot production
(Généthon BioProd). www.genethon.fr
About the Institut de Myologie
The Institut de Myologie is located at Pitié-Salpêtriere University Medical Center in Paris. It was
founded in 1996 by the AFM, in collaboration with the AP-HP public hospitals group, the INSERM
French national institutes of health, Pierre and Marie Curie University, the CEA Atomic Energy
Commission and the CNRS national research institute (since 2009, in the latter case). It brings
together almost 300 expert physicians, researchers and engineers in the field of myology and is an
international center of excellence for the diagnosis, study and treatment of neuromuscular
diseases, the generation of basic scientific knowledge and novel therapeutic approaches (including
biotherapies) and the organization of clinical trials. At present, 31 clinical studies are being run at
the Institute.
About the AP-HP
The Assistance Publique-Hôpitaux de Paris (AP-HP) is the University medical center of the Paris-Ile
de France region. In this respect, it provides comprehensive medical care while running the
research and teaching projects that will shape the medicine of the future. The AP-HP exports its
expertise in medicine, hospital care and other aspects of healthcare worldwide. The group is
comprised of 37 hospitals (including 3 outside Paris) and a home care organization.
Key figures:
- 7 million patients treated each year, including 1 million in the emergency room.
- over 2700 collaborative research projects (800 of which are led by the AP-HP) and over
26,000 patients enrolled in clinical trials.
- 3,000 interns and 13,000 medical students and students in other healthcare-related
sectors.
About the UPMC
The Université Pierre et Marie Curie (UPMC, Pierre and Marie Curie University) is the top-ranked
French university and number 8 in Europe (according to the Taiwan Academic Ranking of
Universities). The UPMC is the largest scientific and medical university complex in France. All the
major scientific and medical disciplines are covered at the university's 18 locations: chemistry,
electronics, computer science, mathematics, mechanical engineering, physics, the earth and
environmental sciences, life science and medicine. Along with Pantheon-Assas Paris 2 University
and Sorbonne Paris 4 University, the UPMC is a founder member of the "Sorbonne Universities"
scientific cooperation foundation.
Key figures for the UPMC: a university community of 10,500 UPMC and seconded staff, including
8,200 in research; 32,000 students, including 7,000 foreign students; 2,000 masters graduates
each year; 250 engineering graduates each year; 126 labs; 3,400 graduate students and 800 PhD
theses each year. The university also encompasses the elite Polytech Paris UPMC engineering
school.
Press contacts:
AFM – Généthon
Anne-Sophie Midol, Stéphanie Bardon, Géraldine Broudin – Tel.: +33 169 472 828
presse@afm.genethon.fr
ALIZE RP
Caroline Carmagnol – Mobile/Cellular: +33 664 189 959 / Tel.: +33 142 688 643 /
caroline@alizerp.com
Anne-Sophie Cosquéric – Tel.: +33 142 688 641 – anne-sophie@alizerp.com