AAV9-Mediated Intrastriatal Delivery of Reduces Hyperlocomotion in Heterozygous R209H Mutant Mice.

Mutations in the gene, which encodes the abundant brain G-protein G , result in neurologic disorders characterized by developmental delay, epilepsy, and movement abnormalities. There are over 50 mutant alleles associated with disorders; the R209H mutation results in dystonia, choreoathetosis, and developmental delay without seizures. Mice heterozygous for the human mutant allele ( ) exhibit hyperactivity in open field tests but no seizures. We developed self-complementary adeno-associated virus serotype 9 (scAAV9) vectors expressing two splice variants of human G isoforms 1 (GA, ) and 2 (GB, ). Bilateral intrastriatal injections of either scAAV9- or scAAV9- significantly reversed mutation-associated hyperactivity in open field tests. overexpression did not increase seizure susceptibility, a potential side effect of vector treatment. This represents the first report of successful preclinical gene therapy for encephalopathy applied in vivo. Further studies are needed to uncover the molecular mechanism that results in behavior improvements after scAAV9-mediated G expression and to refine the vector design. SIGNIFICANCE STATEMENT: mutations cause a spectrum of developmental, epilepsy, and movement disorders. Here we show that intrastriatal delivery of scAAV9- to express the wild-type G protein reduces the hyperactivity of the mouse model, which carries one of the most common movement disorder-associated mutations. This is the first report of a gene therapy for encephalopathy applied in vivo on a patient-allele model.