Limb-Girdle Muscular Dystrophy type R5 is an autosomal recessive disease caused by mutations in the gene encoding the gamma-sarcoglycan (SGCG). Mutations in any of the sarcoglycan genes perturb assembly of the dystrophin-associated glycoprotein complex (DAGC), leading to deficiency of other sarcoglycans and dystrophin, and destabilization of the sarcolemma.
LGMDR5 is the most severe and rapidly progressive form of LGMDs, particularly in patients with onset of symptoms in early childhood. The disease is characterized by progressive proximal muscle weakness. There is involvement of skeletal, cardiac, and respiratory muscles. Most patients lose ambulation during the mid-teens. Diagnosis is based on clinical presentation, immunohistochemistry on muscle biopsy samples, and genetic testing.
Pre-clinical studies support a systemic gene therapy approach for LGMDR5. In SGCG knockout mouse models, a single intravenous administration of ATA-200 at a dose of 1.0E14 vg/kg restored key histological and functional disease parameters to levels comparable to wild-type controls. The minimal effective dose of ATA-200 was established at 1.0E14 vg/Kg.
ATA-003-GSAR is an ongoing Phase 1 study evaluating the safety, tolerability, and preliminary efficacy of ATA-200, an adeno-associated virus vector (AAV) serotype 8 carrying the human SGCG gene for the treatment of LGMDR5 (NCT05973630). Safety, functional assessments and clinical outcomes, muscle MRI, quality of life measures, and biomarkers, including muscle biopsy at 6 months, will be assessed over the 5-year follow-up of the study. Eligible participants are ambulant children younger than 13 years without pre- neutralizing anti-AAV8 antibodies.
Four (4) patients were treated at dose of 1.0E+14 vg/kg between April 2025 and January 2026. All patients received corticosteroids and sirolimus from the day of infusion onward. ATA-200 was generally well tolerated. Except for mild to moderate nausea/vomiting over the first 3-4 days following administration, no adverse events were reported in any patients. Close monitoring of safety parameters and cardiac biomarkers did not reveal any lab abnormalities. The 6-month clinical and biopsy data of the first two patients were just analyzed and will be presented, along with safety status of the 4 patients treated. These tremendous data confirm target engagement with widespread expression of gamma-sarcoglycan, with very high proportion of SGCG-positive fibers.