Enhancing Survival and Alleviating Behavioral Deficits in MeCP2 Null Mice Through Rett Syndrome Gene Therapy

The primary goal of this research was to create a gene therapy for Rett Syndrome, a neurodevelopmental disorder predominantly affecting girls with a frequency of about 1 in 10,000. The condition leads to a decline in developmental milestones such as speech and motor skills, starting from 6 to 18 months of age. Affected individuals typically live for 40 to 50 years but require extensive support and constant care due to lifelong disability.

Rett Syndrome is caused by mutations in the MeCP2 gene, which is responsible for a transcription factor that regulates numerous brain genes. Studies using animal models have shown that restoring MeCP2 expression can alleviate symptoms similar to Rett Syndrome, suggesting the potential of gene therapy.

The researchers developed AVXS-201, a self-complementary adeno-associated virus type 9 vector designed to express the human MeCP2 gene. The vector's efficacy was assessed in male mice, both MeCP2-deficient and normal, and safety and dosage studies were conducted in male non-human primates (Macaca fascicularis). Mice received intracerebroventricular injections of varying doses, and their behavior and survival were closely monitored. Similarly, the weight, blood, and liver parameters of juvenile primates were tracked after receiving lumbar intrathecal injections of AVXS-201.

The results indicated that all tested doses of scAAV9.MeCP2 significantly increased the survival rate of MeCP2-deficient mice and reversed behavioral symptoms, with higher doses enhancing survival by more than 300%. In primates, there were no abnormalities in weight, blood parameters, or liver enzymes up to 18 months post-treatment, and no pathological signs were detected in those sacrificed five weeks post-injection. The treatment demonstrated effective MeCP2 expression throughout the central nervous system following a single injection.

The conclusion of the study is that AVXS-201 is capable of restoring MECP2 expression and is a candidate for further testing in human trials. The disclosure section notes that several researchers have no conflicts of interest, while others have received compensation or hold stock in AveXis, a Novartis company, which sponsored the research.