Efficacy and preliminary safety assessment of EXG001-307 AAV gene therapy for spinal muscular atrophy.

Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disorder characterized by progressive muscular weakness due to the loss of lower motor neurons. The most severe and common form, SMA type 1 (Werdnig-Hoffmann disease), is a devastating childhood condition. Exegenesis Bio is developing EXG001-307, a recombinant adeno-associated virus (rAAV) gene therapy, for SMA type 1 patients lacking functional SMN1 and possessing only 1-2 copies of SMN2. EXG001-307 is an AAV9-based gene therapy vector containing a human SMN cDNA expression cassette driven by a neuron-specific promoter (human synapsin promoter) with cytomegalovirus (CMV) enhancer. In preclinical studies using an SMA mouse model, EXG001-307 demonstrated significant therapeutic efficacy, as evidenced by improved survival rates, enhanced weight gain, and restoration of motor functions. Additionally, EXG001-307 showed reduced transgene expression in the heart, leading to a significantly improved safety profile compared to currently available therapy, without treatment-related deaths even at a very high dose (6 × 1014 vg/kg). Cardiac and hepatic toxicities observed in the benchmark-treated animals were significantly minimized in EXG001-307-treated groups. These results support the continued clinical development of EXG001-307 as a safer and more effective gene therapy for SMA, with ongoing clinical trials (NCT05614531) expected to confirm its therapeutic potential.