The disease affects between 1-in-200,000 to 1-in-350,000 newborns without regard to sex, race, or national origin. The disease is an autosomal recessive genetic disorder, meaning the patient inherited one defective beta-sarcoglycan gene each from both parents. Patients most commonly first present with difficulty running, jumping and climbing stairs at about age 3-5 years. Patients typically become wheelchair dependent in their mid- to late-teens. Respiratory impairment occurs as the disease progresses, leading to the need for ventilator assistance. Scoliosis and joint contractures develop over time as well. Cardiac muscle involvement and decline is also fairly typical. Patients often succumb to the continuing muscle deterioration in their late 20’s to early 30’s. There is not currently any cure or treatment for LGMD2E.
The goal of gene therapy for LGMD2E is to permanently enable the muscle cells to produce the critical beta-sarcoglycan protein, after intravenous administration of a vector containing the beta-sarcoglycan gene and a promoter that only turns on the gene in muscle cells. Establishment of beta-sarcoglycan 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 with confirmed LGMD2E from genetic testing.
Studies of treatment with the gene therapy in the lab of L. Rodino-Klapac at Nationwide Children’s Hospital, in a beta-sarcoglycan production deficient mouse model, resulted in greater than 95% of muscle cells producing the protein, normalization of strength and resistance to fatigue in the diaphragm, decreased contraction-induced injury, and normalized cardiac output. Treatment with the gene therapy was associated with increase in muscle fiber diameters, and a decrease in muscle scarring and fat infiltration. Treatment of beta-sarcoglycan deficient mice with the gene therapy was also associated with increase in overall activity versus non-treated mice. Treatment of normal, healthy, non-human primates with the gene therapy showed distribution and overexpression of the beta-sarcoglycan protein in muscles throughout the body without any adverse effects; no testing for functional changes were done since these were not beta-sarcoglycan deficient animals.
An IND has been approved enable initiation of systemic i.v. testing of the gene therapy in LGMD2E patients, and dosing is expected to be initiated in the second-half of 2018.