DMD TREATMENT: ANIMAL MODELS: P.200Assessment of efficacy of a rAAV9-mini-dystrophin gene therapy candidate (PF-06939926) administered to aged DMDmdx rats

Abstract

We previously determined the effective dose of rAAV9-dys3978 (PF-06939926), a recombinant AAV9 vector expressing a human mini-dystrophin gene under the control of a muscle-specific promoter, administered intravenously to 2 months old DMDmdx rats. An extensive natural history assessment of the DMDmdx rat model also reported a more aggressive phenotype than the mdx mouse model in both skeletal and cardiac muscle tissues, which progressed unfavourably with age. To understand the range of disease severity over which PF-06939926 has the potential to impact disease, we administered this gene therapy candidate to DMDmdx rats at 4 and 6 months of age. All treatment groups were euthanized 3 months after treatment. Despite evidence of transduction efficiency similar to that seen previously in DMDmdx rats treated at 2 months, there was only a trend towards improved fibrosis in the biceps femoris, in the DMDmdx rats treated at 4 months old and little or no impact on the fibrosis in the diaphragm in this group or in both muscles in rats treated at 6 months old. Interestingly, fibrosis in the heart was significantly improved in the rats treated at 4 months old with non-significant trends for reduced fibrosis in the heart of rats treated at 6 months old. Importantly, functional efficacy in skeletal muscle as measured by the grip force test and in the heart by 2D echocardiography, was achieved in both groups. Greater strength and less fatigue were observed in the forelimbs of the DMDmdx rats treated at 4 months old, compared to the 6 months old treated group. In the heart, PF-06939926 effectively corrected DMD-related cardiac pathology and functional deficits in both 4 and 6 months old treated DMDmdx rats. In summary, together with the results from the 2 months old DMDmdx rat treatment study, these findings suggest that administration of PF-06939926 to younger DMDmdx rats induced a greater amelioration of the associated DMD tissue pathology and functional deficits compared to older DMDmdx rats receiving the vector. Importantly, the older rats remained responsive to the vector, especially in the heart. These data may assist in the design of future clinical trials with PF-06939926 in DMD patients with more advanced disease.