%0 Journal Article
%T Gene Therapy Preserves Retinal Structure and Function in a Mouse Model of NMNAT1-Associated Retinal Degeneration.
%A Greenwald SH
%A Brown EE
%A Scandura MJ
%A Hennessey E
%A Farmer R
%A Pawlyk BS
%A Xiao R
%A Vandenberghe LH
%A Pierce EA
%J Mol Ther Methods Clin Dev
%V 18
%N 0
%D Sep 2020 11
%M 32775493
%F 5.849
%R 10.1016/j.omtm.2020.07.003
%X No treatment is available for nicotinamide mononucleotide adenylyltransferase 1 (NMNAT1)-associated retinal degeneration, an inherited disease that leads to severe vision loss early in life. Although the causative gene, NMNAT1, plays an essential role in nuclear nicotinamide adenine dinucleotide (NAD)+ metabolism in tissues throughout the body, NMNAT1-associated disease is isolated to the retina. Since this condition is recessive, supplementing the retina with a normal copy of NMNAT1 should protect vulnerable cells from disease progression. We tested this hypothesis in a mouse model that harbors the p.Val9Met mutation in Nmnat1 and consequently develops a retinal degenerative phenotype that recapitulates key features of the human disease. Gene augmentation therapy, delivered by subretinal injection of adeno-associated virus (AAV) carrying a normal human copy of NMNAT1, rescued retinal structure and function. Due to the early-onset profile of the phenotype, a rapidly activating self-complementary AAV was required to initiate transgene expression during the narrow therapeutic window. These data represent the first proof of concept for a therapy to treat patients with NMNAT1-associated disease.