Efficient delivery of FMR1 across the blood brain barrier using AAVphp construct in adult FMR1 KO mice demonstrates the feasibility of gene therapy for fragile X syndrome

Background Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability and autism. Gene therapy may offer an efficient method to ameliorate symptoms of the disorder. Methods An AAVphp.eb-hSyn-mFMR1IOS7 vector and an empty control were injected in the tail vein of Fmr1 knock out (KO) mouse and wildtype (WT) controls. KO mice were injected with 2 × 1013 vg/kg of the construct. Control KO and WT mice were injected with empty vector. After treatment the animals underwent a battery of tests: open field, marble burying, rotarod, and fear conditioning. Mouse brains were studied for levels of the Fmr1 product, FMRP. Results Significant levels of FMRP were not found outside the CNS in treated animals. The gene delivery was highly efficient, where it exceeded the control FMRP levels in all tested brain regions. There was also improved performance in the rotarod test and partial improvements on other tests in the treated KO animals. Conclusion These experiments demonstrate efficient, brain-specific delivery of Fmr1 via peripheral administration in adult mice. The gene delivery led to partial alleviation of the Fmr1 KO phenotypical behaviors. FMRP oversupply may explain why not all behaviors were significantly affected. Since AAV.php vectors are less efficient in humans than the mice used in the current experiment, studies to determine the optimal dose and using human suitable vectors will be necessary to further demonstrate feasibility.