Retinoic acid related orphan receptor α is a genetic modifier that rescues retinal degeneration in a mouse model of Stargardt disease and Dry AMD.
Monica AkulaS M McNameeZ LoveN NasratyN P M ChanM WhalenM O AvolaA M OlivaresB D LeehyA S JelcickP SinghA K UpadhyayDong Feng ChenNeena B HaiderPublished in: Gene therapy (2024)
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.
Keyphrases
- age related macular degeneration
- early onset
- late onset
- optical coherence tomography
- gene therapy
- diabetic retinopathy
- mouse model
- inflammatory response
- binding protein
- poor prognosis
- oxidative stress
- optic nerve
- type diabetes
- metabolic syndrome
- high fat diet induced
- toll like receptor
- lipopolysaccharide induced
- copy number
- transcription factor
- long non coding rna
- nk cells
- newly diagnosed
- wild type