Rett syndrome gene therapy improves survival and ameliorates behavioral phenotypes in MeCP2 null (S51.002)

Objective: Develop a gene replacement therapy for the treatment of Rett Syndrome. Background: Rett syndrome is a progressive neurodevelopmental disorder, affecting approximately 1 in 10,000 girls. Rett patients experience loss of achieved developmental milestones, including speech and motor function, beginning at 6–18 months of age. Patients often survive for 40–50 years but experience lifelong disability requiring intense supportive measures and 24/7 care. Rett syndrome is caused by mutations in the X-linked methyl-CpG binding protein 2 ( MeCP2 ) gene, encoding a ubiquitous transcription factor with activating and repressing functions for thousands of genes in the brain. Recent studies using rodent models demonstrated that re-expression of MeCP2 ameliorates Rett-syndrome-like phenotypes. Therefore, a gene replacement therapy is a promising therapeutic strategy for this disease. Design/Methods: We generated AVXS-201, a self-complementary adeno-associated virus serotype 9 vector expressing the human MeCP2 gene under the control of a minimal MeCP2 -promoter. We determined the efficacy in male mice (MeCP2-null and wild-type) and performed safety and dose ranging studies in male non-human primates (NHPs; Macaca fascicularis ). Mice were injected intracerebroventricularly with multiple doses, and behavior (e.g., rotarod and open field) and survival were monitored. Weight gain as well as blood and liver parameters of five juvenile NHPs were monitored after lumbar intrathecal injection of AVXS-201. Results: We found that all doses of scAAV9.MeCP2 tested in MeCP2-null mice increased survival and rescued behavioral symptoms with multiple doses improving survival by >300%. In NHPs, weight, blood parameters and liver enzymes remained normal through 18 months post treatment. No indications of pathology were found in the NHPs that were sacrificed at 5 weeks post injection. Overall, our results show good expression of MeCP2 throughout the whole central nervous system after a single injection. Conclusions: AVXS-201 restores MECP2 expression and will be advanced for FIH testing. Disclosure: Dr. Powers has nothing to disclose. Dr. Miranda has nothing to disclose. Dr. Dennys-Rivers has nothing to disclose. Dr. Huffenberger has nothing to disclose. Dr. Braun has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, a Novartis company. Dr. Rinaldi has nothing to disclose. Dr. Wein has nothing to disclose. Dr. Meyer has received royalty, license fees, or contractual rights payments from Celenex/Amicus. Dr. Meyer has received research support from Sanofi. Dr. Solano has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis. Dr. Nguyen has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities as an employee of AveXis, a Novartis company. Dr. Nguyen holds stock and/or stock options in AveXis, a Novartis company which sponsored research in which Dr. Nguyen was involved as an investigator. . Dr. Lang has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, a Novartis company. Dr. Kaspar has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, a Novartis company. Dr. Foust has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employee of AveXis, a Novartis company. Dr. Thomsen has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, a Novartis company. Dr. Thomsen holds stock and/or stock options in AveXis, a Novartis company which sponsored research in which Dr. Thomsen was involved as an investigator. Dr. Thomsen has received research support from AveXis, a Novartis company. Dr. Fugere has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employee of AveXis, a Novartis company. Dr. Kaspar has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, a Novartis company.