Talk abstracts
Talk on Tuesday 04:15-04:30pm submitted by Samantha Powers
Gene therapy for Rett syndrome rescues MeCP2 null mice
Samantha Powers (Neuroscience Graduate Program), Carlos Miranda, Cassandra Dennys, Amy Huffenberger, Lyndsey Braun, Stephanie Solano, Katelynn Kinley, Kimberly Sandy, Kathrin Meyer, Kevin Foust (Nationwide Childrens Hospital Center for Gene Therapy)
Abstract:
Rett syndrome is a devastating progressive neurodevelopmental disorder affecting approximately 1 in 10,000 girls. It is characterized by loss of developmental milestones, autistic behavior, loss of motor function and death at 40-50 years. Rett syndrome is caused by mutations in the methyl-CpG binding protein 2 (MECP2) gene encoding a transcription factor. Recent studies using rodent models demonstrated that re-expression of MeCP2 ameliorates negative Rett syndrome-like phenotypes. Thus, gene therapy is a promising therapeutic strategy for this disease. We have generated an adeno-associated virus (AAV) serotype 9 vector (AAV9-P546-MeCP2) expressing the human MeCP2 gene under the control of a truncated MeCP2-promoter. We determined efficacy and safety of this vector in mice (MeCP2 null and WT) and non-human primates (NHPs). Mice were injected intracerebroventricularly with multiple doses of the vector and behavior and survival were monitored. Weight gain, blood and liver parameters of 5 juvenile NHPs (M. fascicularis) were monitored after lumbar intrathecal injection of AAV9-P546-MeCP2. To date, 2 NHPs were sacrificed for transgene expression and pathology evaluation. All doses of AAV9-P546-MeCP2 tested in MeCP2 null mice increased survival and rescued behavioral symptoms. The most promising dose increased the median lifespan from 66 to 315 days. No toxicity was observed in WT mice. In NHPs, weight development, blood parameters, and liver enzymes remained normal up to 16 months post treatment. No indications of pathology were found in the two NHPs that were sacrificed at 5 weeks post injection. Our results show good expression of MeCP2 after single injection. In MeCP2 null mice, treatment more than quadrupled the lifespan, indicating its high therapeutic potential. Completion of this work will allow IND enabling mouse and NHP safety studies with the goal of initiating a clinical trial in the near future.
Keywords: Rett Syndrome, Gene Therapy, AAV9