Gene therapy using an ortholog of human fragile X mental retardation protein partially rescues behavioral abnormalities and EEG activity

Alexander W M Hooper; Hayes Wong; Yosuke Niibori; Rozita Abdoli; Subha Karumuthil-Melethil; Chunping Qiao; Olivier Danos; Joseph T Bruder; David R Hampson

doi:10.1016/j.omtm.2021.06.013

Gene therapy using an ortholog of human fragile X mental retardation protein partially rescues behavioral abnormalities and EEG activity

Mol Ther Methods Clin Dev. 2021 Jul 16:22:196-209. doi: 10.1016/j.omtm.2021.06.013. eCollection 2021 Sep 10.

Authors

Alexander W M Hooper¹, Hayes Wong¹, Yosuke Niibori¹, Rozita Abdoli¹, Subha Karumuthil-Melethil², Chunping Qiao², Olivier Danos², Joseph T Bruder², David R Hampson^{1

3}

Affiliations

¹ Leslie Dan Faculty of Pharmacy, Department of Pharmaceutical Sciences, University of Toronto, Toronto, Ontario, Canada M5S 3M2.
² Research and Early Development, REGENXBIO Inc. Rockville, Maryland, U.S.A. 20850.
³ Department of Pharmacology and Toxicology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada M5S 3M2.

Abstract

Fragile X syndrome (FXS), a neurodevelopmental disorder with no known cure, is caused by a lack of expression of the fragile X mental retardation protein (FMRP). As a single-gene disorder, FXS is an excellent candidate for viral-vector-based gene therapy, although that is complicated by the existence of multiple isoforms of FMRP, whose individual cellular functions are unknown. We studied the effects of rat and mouse orthologs of human isoform 17, a major expressed isoform of FMRP. Injection of neonatal Fmr1 knockout rats and mice with adeno-associated viral vectors (AAV9 serotype) under the control of an MeCP2 mini-promoter resulted in widespread distribution of the FMRP transgenes throughout the telencephalon and diencephalon. Transgene expression occurred mainly in non-GABAergic neurons, with little expression in glia. Early postnatal treatment resulted in partial rescue of the Fmr1 KO rat phenotype, including improved social dominance in treated Fmr1 KO females and partial rescue of locomotor activity in males. Electro-encephalogram (EEG) recordings showed correction of abnormal slow-wave activity during the sleep-like state in male Fmr1 KO rats. These findings support the use of AAV-based gene therapy as a treatment for FXS and specifically demonstrate the potential therapeutic benefit of human FMRP isoform 17 orthologs.

Keywords: AAV; EEG; GABA; autism; cerebrospinal fluid; epilepsy; interneurons; sleep; viral vector; virus.