Treatment for Gama-Sarcoglycanopathy

Gamma-Sarcoglycanopathy (LGMD2C) is one of the most common limb-girdle myopathies. It affects less than 10 people per 1,000,000 and is characterized by progressive muscle weakness in the pelvis (pelvic girdle) and shoulders (scapular girdle), linked to mutations in the SGCG gene encoding gamma-sarcoglycan. There is currently no cure for this neuromuscular disease.

Sarcoglycanopathies are rare autosomic limb girdle muscular dystrophies causing  mutations in one of the genes coding for sarcoglycans. Sarcoglycans form a complex, which is an important part of the dystrophin-associated glycoprotein complex; which protects the sarcolemma against muscle contraction-induced damage. Absence of one of the sarcoglycan on the plasma membrane reduces the stability of the whole complex and perturbs muscle fiber membrane integrity.

There is currently no curative treatment for any of the Sarcoglycanopathies. This study is the result of several years of work. Indeed; we had already tested another vector that proved to be well tolerated but with limited gene expression. Determined the effective treatment dose.

Deficient SGCG Gene

The drug vector restored, with the highest dose, an almost complete expression of the deficient SGCG gene. The researchers observed that the proportion of corrected muscle fibres is less than 5% with the lowest dose;between 25% and 75% with the intermediate dose and between 75% and 100% with the highest dose.

But in some viral production is validating by intramuscular injection into the tibialis anterior (TA) of four-week old male Sgcg-/- mice (n=3 animals per group) with a dose of 1×1010 viral genome (vg)/TA. After one month; muscles are sampled and SGCG expression is determining by immunohistochemistry analysis of transversal sections.


Comparing to AAV1, the AAV8 serotype was reporting to have better efficiency in the transduction of striated muscles. But this initial clinical trials for neuromuscular diseases is limiting to an intramuscular route of administrating for safety reasons; but the field is now moving towards systemic administration, thanks to encouraging results from pioneer clinical studies such as the SMA or MTM1 trials (NCT02122952 and NCT03199469).

This mode of administration seems mandatory in sarcoglycanopathies for reaching therapeutic levels, since the skeletal muscle constitutes approximately 40% of the human body, and some muscles, such as the diaphragm;the intercostal muscles and the heart; are hardly accessible by skeletal muscle injections.Thus, the overall conclusion from the present investigation is that our viral vector might be suited for future clinical trials with human patients.