title: Reduced phenotypic severity following adeno-associated virus-mediated Fmr1 gene delivery in fragile X mice.
abstract: Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by a trinucleotide repeat expansion in the FMR1 gene that codes for fragile X mental retardation protein (FMRP). To determine if FMRP expression in the central nervous system could reverse phenotypic deficits in the Fmr1 knockout (KO) mouse model of FXS, we used a single-stranded adeno-associated viral (AAV) vector with viral capsids from serotype 9 that contained a major isoform of FMRP. FMRP transgene expression was driven by the neuron-selective synapsin-1 promoter. The vector was delivered to the brain via a single bilateral intracerebroventricular injection into neonatal Fmr1 KO mice and transgene expression and behavioral assessments were conducted 22-26 or 50-56 days post injection. Western blotting and immunocytochemical analyses of AAV-FMRP-injected mice revealed FMRP expression in the striatum, hippocampus, retrosplenial cortex, and cingulate cortex. Cellular expression was selective for neurons and reached ∼ 50% of wild-type levels in the hippocampus and cortex at 56 days post injection. The pathologically elevated repetitive behavior and the deficit in social dominance behavior seen in phosphate-buffered saline-injected Fmr1 KO mice were reversed in AAV-FMRP-injected mice. These results provide the first proof of principle that gene therapy can correct specific behavioral abnormalities in the mouse model of FXS.
authors.affiliation: Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON, Canada.
authors.forename: Shervin
authors.initials: S
authors.lastname: Gholizadeh
authors.affiliation: Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON, Canada.
authors.forename: Jason
authors.initials: J
authors.lastname: Arsenault
authors.affiliation: Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON, Canada.
authors.forename: Ingrid Cong Yang
authors.initials: IC
authors.lastname: Xuan
authors.affiliation: Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON, Canada.
authors.forename: Laura K
authors.initials: LK
authors.lastname: Pacey
authors.affiliation: 1] Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON, Canada [2] Department of Pharmacology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
authors.forename: David R
authors.initials: DR
authors.lastname: Hampson
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D000229:Dependovirus / Q000235:genetics / Q000502:physiology*; D004195:Disease Models, Animal; D020195:Epilepsy, Reflex / Q000209:etiology; D005260:Female; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics / Q000378:metabolism*; D005600:Fragile X Syndrome / Q000150:complications / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D005786:Gene Expression Regulation / Q000235:genetics; D005822:Genetic Vectors / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity / Q000502:physiology; D010641:Phenotype; D012930:Social Dominance; D018709:Statistics, Nonparametric; D013239:Stereotyped Behavior / Q000502:physiology; D014828:Vocalization, Animal
chemical_list: D051860:Fragile X Messenger Ribonucleoprotein 1; C497684:Fmr1 protein, mouse