Abstract
Purpose :
In animal models of cone/rod dystrophies (CRDs), enhanced activation of the retinoic acid receptor (RAR) has been shown to cause detrimental remodeling and retinal hyperactivity, further degrading vision. However, these findings have not been recapitulated in humans. RAR is a nuclear transcription factor regulating the expression of many genes, including micro-RNAs (miRNA). Human vitreous is rich in miRNAs that are secreted by retinal cells. Here we seek to provide direct evidence for the upregulation of RAR in patients with CRDs by characterizing miRNAs that are regulated by RAR.
Methods :
Human vitreous biopsies were collected during routine, clinically-indicated vitrectomy. Patients were divided into two cohorts: (1) retinal degeneration (RD), including retinal detachment and age-related macular degeneration; or (2) no retinal degeneration (control), including epiretinal membrane and dislocated intraocular lens. Samples were complemented by optical coherence tomography (OCT) imaging. In parallel, retinal samples were collected from wild-type and blind (Pde6brd1/rd1) mice intravitreally treated with RAR agonists or antagonists. MiRNAs were extracted from each sample using the miRNeasy kit (Qiagen) and amplified using the Taqman miRNA Assay (Thermo Fisher).
Results :
An initial literature review to identify surrogates for RAR expression determined that RAR downregulates miR-20b and upregulates miR-132. In the vitreous biopsies, the expression of miR-20b decreased by 60-70% in RD patients, while miR-132 showed a 5-fold increase. These results confirm the hyperactivation of RAR-dependent transcription during photoreceptor loss. Testing of further patients is underway examining an expanded panel of marker miRNAs. Pharmacological manipulation of RAR-activation in WT and Pde6brd1/rd1 mouse retinas confirms the causal relationship between the selected miRNAs and RAR-dependent signaling.
Conclusions :
These findings support the claim that CRDs cause detrimental remodeling and neuronal hyperactivity in human retinas. We propose that miRNAs can be used as biomarkers for retinal remodeling and RAR-dependent activity. Modulation of remodeling by targeting RAR-downstream molecules such as miRNA may represent a novel treatment in retinal degeneration.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.