Dr. Michael Sinnreich
Development of therapeutic strategies for dysferlin deficiency
Dr. Michael Sinnreich, a neurologist and neuroscientist, is the director of the Molecular Diagnostic Laboratory for Neuromuscular Diseases at the Montreal Neurological Institute. His research interests are in the neuromuscular field and they focus mainly on the molecular aspects of Limb Girdle Muscular Dystrophies. Dr. Sinnreich shares the neuromuscular clinic at the Montreal Neurological Hospital with Dr. George Karpati, and the peripheral nerve clinic at the Montreal General Hospital with Dr. Colin Chalk. He performs clinical electrophysiological testing and participates in the interpretation of diagnostic nerve and muscle biopsies.
Dr. Sinnreich’s current research project funded through the Neuromuscular Research Partnership is focused on the development of therapeutic strategies for dysferlin deficiency. Dysferlin is a transmembrane protein implicated in the repair of naturally occurring surface muscle membrane tears. Mutations in the dysferlin gene cause the recessively inherited Limb Girdle Muscular Dystrophy type 2B (LGMD2B) and the distal Miyoshi Myopathy (MM). No therapy is currently available for patients with dysferlin deficiency. His research lab is developing and testing recombinant micro-dysferlin molecules as a potential gene replacement therapy for patients affected by these diseases.
As dysferlinopathies are recessively inherited diseases, dysferlin gene replacement therapy could be an effective treatment that would not require correction of the mutated allele. Promising gene delivery strategies for skeletal muscle diseases include adeno-associated viral (AAV) vectors, given their high muscle tropism, low immunogenicity and non-pathogenicity. Because of their limited insert capacity, full length dysferlin cDNA cannot be incorporated into AAV. Therefore, his goal is to design functionally active small recombinant dysferlin molecules suitable for AAV delivery. His lab is studying lipid and protein interactions of dysferlin domains to identify functionally and structurally important protein regions. The knowledge gained will help in the design of the recombinant micro-dysferlin constructs. These constructs will be tested in dysferlin deficient human myotubes for their membrane resealing activities in vitro. Transgenic mice will be generated with successful micro-dysferlin candidates and will be backcrossed to dysferlin knock-out mice to alleviate the disease phenotype. These experiments will lay ground for preclinical AAV-mediated gene transfer experiments in mouse models of dysferlinopathies.
