Abstract Details

Rett syndrome gene therapy improves survival and ameliorates behavioral phenotypes in MeCP2 null
Child Neurology and Developmental Neurology
S51 - Child Neurology: Bench to Bedside: Progress in Treating Genetic Disorders (3:41 PM-3:52 PM)
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 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.
Develop a gene replacement therapy for the treatment of Rett Syndrome.
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.  
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. 
AVXS-201 restores MECP2 expression and will be advanced for FIH testing. 
Authors/Disclosures

PRESENTER 		No disclosure on file
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Gretchen Thomsen No disclosure on file
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