Embargoed: not for release until 18:00 hours London time of 15 November 2006
Researchers working at the San Raffaele Scientific Institute demonstrate the efficacy of stem cell therapy in dystrophic dog, an animal model of Duchenne muscular dystrophy.
In collaboration with the Italian charity foundation Telethon, the researchers are planning future clinical trials.
Milan, November 15th 2006 - A research group at the San Raffaele Scientific Institute, in collaboration with the University of Pavia and the Veterinarian School of Macon Alfort (Paris), demonstrated the efficacy of cell therapy with a new class of vessel associated stem cells, named “mesoangioblasts”, transplanted in a dog model for Duchenne muscular dystrophy. Like Duchenne patients, dystrophic dogs develop naturally a severe form of muscular dystrophy, since the protein dystrophin is totally absent from the cell membrane of canine muscular fibers. Mesoangioblasts transplanted systemically in the dystrophic dogs rescued the expression of dystrophin in muscular fibers and ameliorated muscle function.
This important breakthrough is published on line in Nature. An editorial comment by Jeffrey Chamberlain, University of Washington School of Medicine, Seattle, WA, USA, is also included in the same issue of Nature
The paper published on Nature
Duchenne muscular dystrophy remains an untreatable genetic disease that severely limits motility and life expectancy in affected children. The only animal model specifically reproducing the alterations in the dystrophin gene and the full spectrum of human pathology is the golden retriever dog model. Affected animals present a single mutation in intron 6, resulting in complete absence of the dystrophin protein, and early and severe muscle degeneration with nearly complete loss of motility and walking ability. Death usually occurs at about 1 year of age as a result of failure of respiratory muscles. Here we report that intra-arterial delivery of wild-type canine mesoangioblasts (vessel-associated stem cells) results in an extensive recovery of dystrophin expression, normal muscle morphology and function (confirmed by measurement of contraction force on single fibres). The outcome is a remarkable clinical amelioration and preservation of active motility. These data qualify mesoangioblasts as candidates for future stem cell therapy for Duchenne patients.
Previous studies
“This study is the result of a long lasting project started with experiments in dystrophic mice” - underlines Giulio Cossu, Head of Stem Cell Research Institute of San Raffele Scientific Institute, Professor at the University of Milan and coordinator of the experimental project.
In 1998 the authors showed that cells from bone marrow can participate to muscle regeneration. Unfortunately the bone marrow transplantation in dystrophic mice could not ameliorate the dystrophic phenotype. Later, the authors identified vessel associated stem cells named mesoangioblasts, that can be expanded in vitro and differentiate efficiently into muscle cells.
In 2003 these observations lead to the first stem cell therapy in dystrophic mice with positive results. Mesoangioblasts, isolated from wild type mice or from dystrophic mice and genetically corrected in vitro, rescued the dystrophic phenotype of transplanted mice affected by limb girdle muscular dystrophy. These experimental procedures were also improved in order to optimize the colonization of dystrophic muscles by itransplanted stem cells.
“Before starting a clinical trial in humans” - explains prof. Cossu - "we moved from mice to dystrophic dogs in order to optimize the cell therapy protocol; in fact, the dystrophic dog is the only animal model specifically reproducing the full spectrum of Duchenne muscular dystrophy in humans: the results published today in Nature Journal indicate that the cell therapy protocol was in large part successful and support the idea of planning clinical trials in humans. It is important to notice that clinical trials require a long period for the set up and therefore we invite patients to continue their cures under the control of specialists that are routinely informed about the progress in this field.”
One important step already took place: last week a meeting of neurologists, researches and specialists of muscular diseases, was organized at San Raffaele Institute. The aim of meeting was to share the scientific results obtained by Cossu’s group and to begin to organize the future clinical trials. At the meeting were present also Telethon and Duchenne Parent Project Associations.
Duchenne muscular Dystrophy (DMD)
Duchenne muscular dystrophy (DMD) (also known as muscular dystrophy - Duchenne type) is an inherited disorder characterized by rapidly progressive muscle weakness which starts in the legs and pelvis and later affects the whole body. Duchenne muscular dystrophy (DMD) is the most common form of muscular dystrophy. It usually affects only males, but in rare cases it can also affect females. It is an X-linked recessive inherited disease. A milder form of this disease is known as Becker's muscular dystrophy (BMD). In Becker muscular dystrophy, most of the symptoms are similar to Duchenne, but the onset is later and the course is milder. DMD is named after the French neurologist Guillaume Benjamin Amand Duchenne (1806-1875), who first described the disease in the 1860s. One third of the cases are known to be caused by development of spontaneous mutations in the dystrophin gene, while the remainder are inherited. Boys with DMD develop weak muscles because the muscle fibers that were present at birth are progressively destroyed. It is due to mutations in the dystrophin gene, which encodes a cell membrane protein musclefibers . Progressive muscle weakness usually leads patients to wheelchair by the end of the first decade of life and to assisted ventilation by the end of the second. Respiratory and cardiac symptoms usually result in death by age 30. There is no known cure for Duchenne muscular dystrophy. Treatment with steroids is aimed controlling symptoms and maximize the quality of life. Moderate physical activity is encouraged. Inactivity (such as bed rest) can worsen the muscle disease. Physical and occupational therapy may be helpful to maintain muscle strength and function. Orthopaedic appliances (such as braces and wheelchairs) may improve mobility and the ability for self-care.
Funds
Researchers were supported mainly by Telethon foundation. The experimental procedures on dystrophic dogs were mainly supported by AFM (Association Francaise contre les Myopathies). Funds were also obtained from Parent Project Onlus, the Muscular Dystrophy Association of America, the EC network “Eurostemcell”, the Italian Ministry of Health and of Research and Cariplo Foundation.
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PUBBLISHED ON NATURE, NOVEMBER 15TH 2006
Mesoangioblast stem cells ameliorate muscle function in dystrophic dogs
Maurilio Sampaolesi (1,2*), Stephane Blot (3*), Giuseppe D’Antona (2), Nicolas Granger3, Rossana Tonlorenzi (1), Anna Innocenzi (1), Paolo Mognol (4), Jean-Lauren Thibaud (3), Beatriz G. Galvez (1), Ines Barthe´le´my (3), Laura Perani (1), Sara Mantero (4), Maria Guttinger (5), Orietta Pansarasa (2), Chiara Rinaldi (2), M. Gabriella Cusella De Angelis (2), Yvan Torrente (6), Claudio Bordignon (1), Roberto Bottinelli (2) & Giulio Cossu (1,5,7)
*These authors contributed equally to this work
1) San Raffaele Scientific Institute, Università Vita-Salute, Stem Cell Research Institute, Milano
2) Department of Experimental Medicine and Interuniversity Institute of Myology, University of Pavia, Pavia
3) Neurobiology Laboratory, E´cole Ve´te´rinaire d’Alfort. Maisons-Alfort cedex, France.
4) Department of Bioengineering, Politecnico di Milano, Milano.
5) Institute of Cell Biology and Tissue Engineering, San Raffaele Biomedical Science Park di Roma
6) IRCCS Fondazione Policlinico di Milano, Department of Neurological Sciences, University of Milan, Milano
7) Department of Biology and Centre for Stem Cell Research, University of Milan, Milano
