The rate of progression of LGMD2B/Myoshi is fairly slow compared to most other muscular dystrophies but is also characterized by chronic progressive muscle fiber loss, inflammation, and muscle fiber replacement by fat infiltration and fibrotic scars, leading to continually deteriorating muscle strength and function. Dysferlinopathy affects between 1-in-100,000 to 1-in-200,000 newborns worldwide affecting both sexes, all races, and all national origins. The disease is an autosomal recessive genetic disorder, meaning the patient inherited one defective dysferlin gene each from both parents. Typically, patients present in their early 20’s with slowly progressive muscle weakness and high serum levels of a marker of muscle damage (creatine kinase (CK)). As the disease progresses, patients experience muscle weakness in both proximal and distal limbs. Approximately one-third of patients become wheelchair-dependent within 15 years of onset of symptoms and generally progressive challenges in performing activities of daily living. This type of muscular dystrophy does not affect the heart muscle. There is currently no cure or treatment for LGMD2B.
The goal of gene therapy for LGMD2B is to permanently enable the muscle cells to produce the critical dysferlin protein, after simultaneous intravenous administration of two vectors, each containing approximately one-half of the gene; the two halves self-assembling into a complete intact functional gene with a promoter that only turns on the gene in muscle cells. Establishment of functional dysferlin production in the muscle cells is expected to result in significant improvement in symptoms, with greater improvement toward normal the earlier in the disease the treatment is administered, and with the potential to prevent any symptoms of the disease from occurring when administered to newborns and/or young asymptomatic individuals with confirmed LGMD2B based on genetic testing.
Studies of systemic i.v. treatment with the dual vector gene therapy approach, in the lab of L. Rodino-Klapac, in a dysferlin production deficient mouse model resulted in widespread dysferlin expression in all muscles tested. The most affected muscle in the dysferlin production deficient mouse, the psoas, had less inflammation and fibrotic scars following gene therapy than untreated animals. The deficits in diaphragm force that develops in dysferlin deficient mice was prevented by the dual vector gene therapy treatment. There was also a dose-dependent prevention of deficits in diaphragm muscle fiber membrane repair in the treated dysferlin production deficient mice compared to untreated mouse model. Treatment of normal, healthy, non-human primates with the gene therapy showed distribution and overexpression of the dysferlin protein in muscles throughout the body without any adverse effects; no testing for functional changes were done since these were not dysferlin deficient animals.
An IND is currently approved to allow intramuscular administration of the dual vector gene therapy in LGMD2B patients. A request will be submitted in 2019 to amend the IND to progress to systemic i.v. administration of LGMD2B patients.