Martin Fugere, Rajeev Sivasankaran, Susan McQuown, Chang Choi, Katrina Salvador, Shirley Phillips, Yin Gu, Binh Chu, Janet Do, Tsun-Kai Chang, Katherine Nguyen, Yanchi Li, Stephanie Solano, Natalia Teider, Colin Fennelly, Ricardo Dolmetsch, Monica Bennett, Kevin Foust, Page Bouchard; AveXis Research and Development, San Diego, CA, Novartis Institutes for Biomedical Research, Cambridge, MA
For clinical translation, we developed AVXS-401, a self-complementary adenoassociated virus (AAV9) based gene replacement therapy to provide sustained expression of FXN in key tissues relevant to FA. Toxicity studies in wildtype mice proved AVXS-401 is safe and well-tolerated. Dose ranging efficacy studies following a one-time, pre-symptomatic intracerebroventricular (ICV) administration of AVXS-401 in conditional FXN-deficient mice in the CNS (Pvalb) demonstrates amelioration of behavioral phenotypes, rescue of Purkinje neurons and cerebellar gliosis at low doses. ICV delivery of AVXS-401 in cardiac mutants (MCK) results in full recovery of cardiac functions as measured by magnetic resonance imaging (MRI), prevention of histopathological evidence of cardiomyopathy and >300% increase in median survival at efficacious doses.
Scale up of therapeutic doses to non-human primates (NHP) showed that AVXS-401 is safe and well tolerated with no aberrant behavior, clinical or anatomical pathology attributable to frataxin expression. Importantly, AVXS-401 provides durable mRNA transcription in the CNS and heart of NHP at 6 months postinjection with frataxin expression detectable above endogenous levels. Dose escalation studies by intrathecal (IT) administration in NHP show a dose correlation between mice and NHP by ddPCR quantification of vector genomes. Together these pre-clinical data show that AVXS-401 is suitable for first-inhuman studies.
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