Retinoic acid related orphan receptor α is a genetic modifier that rescues retinal degeneration in a mouse model of Stargardt disease and Dry AMD

M Akula; S M McNamee; Z Love; N Nasraty; N P M Chan; M Whalen; M O Avola; A M Olivares; B D Leehy; A S Jelcick; P Singh; A K Upadhyay; D F Chen; N B Haider

doi:10.1038/s41434-024-00455-z

Retinoic acid related orphan receptor α is a genetic modifier that rescues retinal degeneration in a mouse model of Stargardt disease and Dry AMD

Gene Ther. 2024 May 16. doi: 10.1038/s41434-024-00455-z. Online ahead of print.

Authors

M Akula¹, S M McNamee¹, Z Love¹, N Nasraty¹, N P M Chan¹, M Whalen¹, M O Avola¹, A M Olivares¹, B D Leehy¹, A S Jelcick¹, P Singh², A K Upadhyay², D F Chen¹, N B Haider³

Affiliations

¹ Schepens Eye Research Institute, Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA.
² Ocugen, Inc., Malvern, PA, USA.
³ Schepens Eye Research Institute, Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA. neena_haider@hms.harvard.edu.

PMID: 38755404
DOI: 10.1038/s41434-024-00455-z

Abstract

Degeneration of the macula is associated with several overlapping diseases including age-related macular degeneration (AMD) and Stargardt Disease (STGD). Mutations in ATP Binding Cassette Subfamily A Member 4 (ABCA4) are associated with late-onset dry AMD and early-onset STGD. Additionally, both forms of macular degeneration exhibit deposition of subretinal material and photoreceptor degeneration. Retinoic acid related orphan receptor α (RORA) regulates the AMD inflammation pathway that includes ABCA4, CD59, C3 and C5. In this translational study, we examined the efficacy of RORA at attenuating retinal degeneration and improving the inflammatory response in Abca4 knockout (Abca4^-/-) mice. AAV5-hRORA-treated mice showed reduced deposits, restored CD59 expression and attenuated amyloid precursor protein (APP) expression compared with untreated eyes. This molecular rescue correlated with statistically significant improvement in photoreceptor function. This is the first study evaluating the impact of RORA modifier gene therapy on rescuing retinal degeneration. Our studies demonstrate efficacy of RORA in improving STGD and dry AMD-like disease.