Preclinical dose response study shows NR2E3 can attenuate retinal degeneration in the retinitis pigmentosa mouse model Rho P23H

• Published in: Gene therapy Vol. 31; no. 5-6; p. 255
• Main Authors: McNamee, Shannon M, Chan, Natalie P, Akula, Monica, Avola, Marielle O, Whalen, Maiya, Nystuen, Kaden, Singh, Pushpendra, Upadhyay, Arun K, DeAngelis, Margaret M, Haider, Neena B
• Format: Journal Article
• Language: English
• Published: England 01-05-2024
• Subjects: Animals; Disease Models, Animal; Electroretinography; Genetic Therapy - methods; Mice; Orphan Nuclear Receptors - genetics; Retina - metabolism; Retina - pathology; Retinal Degeneration - etiology; Retinal Degeneration - genetics; Retinal Degeneration - metabolism; Retinitis Pigmentosa - genetics; Retinitis Pigmentosa - metabolism
• ISSN: 1476-5462

Retinitis pigmentosa (RP) is a heterogeneous disease and the main cause of vision loss within the group of inherited retinal diseases (IRDs). IRDs are a group of rare disorders caused by mutations in one or more of over 280 genes which ultimately result in blindness. Modifier genes play a key role in modulating disease phenotypes, and mutations in them can affect disease outcomes, rate of progression, and severity. Our previous studies have demonstrated that the nuclear hormone receptor 2 family e, member 3 (Nr2e3) gene reduced disease progression and loss of photoreceptor cell layers in Rho
mice. This follow up, pharmacology study evaluates a longitudinal NR2E3 dose response in the clinically relevant heterozygous Rho
mouse. Reduced retinal degeneration and improved retinal morphology was observed 6 months following treatment evaluating three different NR2E3 doses. Histological and immunohistochemical analysis revealed regions of photoreceptor rescue in the treated retinas of Rho
mice. Functional assessment by electroretinogram (ERG) showed attenuated photoreceptor degeneration with all doses. This study demonstrates the effectiveness of different doses of NR2E3 at reducing retinal degeneration and informs dose selection for clinical trials of Rho
-associated RP.