The disease is an autosomal recessive genetic disorder, meaning the patient inherited one defective alpha-sarcoglycan gene each from both parents. The usual age of onset of symptoms ranges from 3-10 years, but in some cases symptoms don’t appear until early adulthood. A marker of muscle damage (creatine kinase (CK)) is markedly elevated in these patients, with 50 to 100X normal levels not unusual. LGMD2D most often first presents with weakness of muscles in the hip, shoulder and abdomen. Subjects usually become wheelchair dependent by age 13-15. Respiratory impairment occurs as the disease progresses, leading to the need for ventilatory assistance. Scoliosis and joint contractures develop over time as well. There is not currently any cure or treatment for LGMD2D.
The goal of gene therapy for LGMD2D is to permanently enable the muscle cells to produce the critical alpha-sarcoglycan protein, after intravenous administration of a vector containing the alpha-sarcoglycan gene and a promoter that only turns on the gene in muscle cells. Establishment of alpha-sarcoglycan production in the muscle cells is expected to result in significant improvement in symptoms, with greater improvement toward normal ambulatory independence, 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 with confirmed LGMD2D from genetic testing.
Studies of treatment with the gene therapy in the lab of L. Rodino-Klapac at Nationwide Children’s Hospital, in a 4-5 week old alpha-sarcoglycan deficient mouse model, resulted in muscle cells maintaining force comparable to healthy normal mice after treatment with the gene therapy. Physical activity and a marker of muscle damage (creatine kinase (CK)) were also maintained at near normal healthy levels, despite both being significantly adversely affected in untreated alpha-sarcoglycan deficient mice. LGMD2D patients dosed with the proposed gene therapy by direct intramuscular injection, or via intravascular delivery to isolated lower limbs showed expression of the alpha-sarcoglycan protein in muscle fibers exposed to the gene therapy.
The IND will be amended in 2018 to allow systemic i.v. administration of doses expected to be efficacious, and dosing is expected to begin in early 2019.