2026-06-18 カリフォルニア大学リバーサイド校（UCR）
＜関連情報＞
- https://news.ucr.edu/articles/2026/06/18/gene-therapy-reverses-fragile-x-deficits-mice
- https://www.cell.com/molecular-therapy-family/nucleic-acids/fulltext/S2162-2531%2826%2900152-6
ヒトFMRPアイソフォームの新生児期発現は、脆弱X症候群のマウスモデルにおける皮質処理障害を回復させ、行動を改善する Neonatal expression of human FMRP isoform rescues cortical processing deficits and improves behaviors in a mouse model of Fragile X Syndrome
Anna O. Norman ∙ Courtney Scaramella ∙ Dominik Biezonski ∙ … ∙ Jim Selfridge ∙ Stuart Cobb ∙ Iryna M. Ethell
Molecular Therapy Nucleic Acids Published:June 11, 2026
DOI:https://doi.org/10.1016/j.omtn.2026.102981
Graphical abstract
Abstract
Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by CGG trinucleotide repeat expansion in the Fragile X Messenger Ribonucleoprotein 1 (FMR1) gene and the resulting loss of Fragile X messenger ribonucleoprotein (FMRP). Gene therapy using recombinant adeno-associated virus (AAV) to restore FMRP expression, particularly in the brain, is a promising therapeutic strategy targeting the underlying cause of FXS. We examined the impact of AAV serotype 9 (AAV9)-mediated expression of a brain-abundant human FMRP isoform (isoform 7) driven by a fragment of the human FMR1 promoter on circuit and behavioral dysfunctions in the male Fmr1 knockout (KO) mouse, FXS model. Following intracerebroventricular (ICV) injection of AAV9-NG276 into neonatal KO mice at a low (1e11 vg/animal) or high (3e11 vg/animal) dose, we assessed cortical phenotypes using electroencephalography (EEG) recordings and behavioral testing. High-dose AAV9-NG276 normalized baseline gamma power, improved sound-evoked responses, and reduced background neural activity. Analysis of behavioral deficits in adult KO mice showed that high-dose neonatal AAV9-NG276 delivery normalized exploratory behaviors, social preference, and probabilistic reversal learning. Thus, early AAV-mediated delivery of human FMR1 isoform 7 ameliorates cortical dysfunction and behavior deficits in a murine FXS model and suggests widespread cortical biodistribution is required for therapeutic benefit.
