Faculty Collaboration Database

Intravitreal delivery of a novel AAV vector targets ON bipolar cells and restores visual function in a mouse model of complete congenital stationary night blindness. Hum Mol Genet 2015 Nov 01;24(21):6229-39

Date

08/28/2015

Pubmed ID

26310623

Pubmed Central ID

PMC4612567

DOI

10.1093/hmg/ddv341

Scopus ID

2-s2.0-84949238699 (requires institutional sign-in at Scopus site)   58 Citations

Abstract

Adeno-associated virus (AAV) effectively targets therapeutic genes to photoreceptors, pigment epithelia, Müller glia and ganglion cells of the retina. To date, no one has shown the ability to correct, with gene replacement, an inherent defect in bipolar cells (BCs), the excitatory interneurons of the retina. Targeting BCs with gene replacement has been difficult primarily due to the relative inaccessibility of BCs to standard AAV vectors. This approach would be useful for restoration of vision in patients with complete congenital stationary night blindness (CSNB1), where signaling through the ON BCs is eliminated due to mutations in their G-protein-coupled cascade genes. For example, the majority of CSNB1 patients carry a mutation in nyctalopin (NYX), which encodes a protein essential for proper localization of the TRPM1 cation channel required for ON BC light-evoked depolarization. As a group, CSNB1 patients have a normal electroretinogram (ERG) a-wave, indicative of photoreceptor function, but lack a b-wave due to defects in ON BC signaling. Despite retinal dysfunction, the retinas of CSNB1 patients do not degenerate. The Nyx(nob) mouse model of CSNB1 faithfully mimics this phenotype. Here, we show that intravitreally injected, rationally designed AAV2(quadY-F+T-V) containing a novel 'Ple155' promoter drives either GFP or YFP_Nyx in postnatal Nyx(nob) mice. In treated Nyx(nob) retina, robust and targeted Nyx transgene expression in ON BCs partially restored the ERG b-wave and, at the cellular level, signaling in ON BCs. Our results support the potential for gene delivery to BCs and gene replacement therapy in human CSNB1.

Author List

Scalabrino ML, Boye SL, Fransen KM, Noel JM, Dyka FM, Min SH, Ruan Q, De Leeuw CN, Simpson EM, Gregg RG, McCall MA, Peachey NS, Boye SE

Author

Miranda L. Scalabrino PhD Assistant Professor in the Ophthalmology and Visual Sciences department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Dependovirus
Disease Models, Animal
Eye Diseases, Hereditary
Genetic Diseases, X-Linked
Genetic Vectors
Humans
Intravitreal Injections
Mice
Mice, Inbred C57BL
Mutation
Myopia
Night Blindness
Promoter Regions, Genetic
Proteoglycans
Retina
Retinal Bipolar Cells
Transfection
Transgenes
Vision, Ocular