Effects of microRNA overexpression on cone photoreceptor survival and structure in health and disease

Abstract

Inherited retinal diseases (IRDs) and age-related macular degeneration (AMD) are characterized by the loss of photoreceptors, the sensory neurons in the retina, leading to severe vision loss. Retinitis pigmentosa (RP), the most common IRD, involves mutations in more than 80 known genes, while AMD affects older individuals and is associated with both genetic and environmental risk factors. Central vision loss, primarily caused by cone degeneration in the central parts of the retina, severely impacts quality of life due to loss of high acuity vision. Given the complexity of genetic and non-genetic factors involved in disease development, gene therapy approaches are often impractical, highlighting the need for gene-independent therapeutic approaches. <br /> This study investigated the neuroprotective role of specific neuronal microRNAs (miRNA), miR-124, miR-182 and miR-183, on cone photoreceptors in the retinal degeneration mouse 1 (rd1) model of RP, as a gene-independent approach. In addition, the potential of miR-183 to accelerate cone photoreceptor development was investigated using stem cell-derived human retinal organoids (hRO). The goal was to enhance cone maturation to overcome the time-delayed development of photoreceptors and retinal ganglion cells (RGCs) that currently limits advanced functional analysis. <br /> Subretinal injections of adeno-associated viral (AAV) vectors encoding miR-124, miR-182 and miR-183 were performed at different stages of disease and retinal development in rd1 mice. miR-124 demonstrated promising effects, resulting in trends toward improved light aversion behavior after treatment, regardless of disease or retinal developmental stage. miR-182 and miR-183 treatment also resulted in trends toward improved light aversion behavior after treatment, although their efficacy seemed to depend on retinal developmental stage. In hROs, miR-183 significantly increased cone protrusion lengths, demonstrating its potential to enhance cone photoreceptor development in growing hROs. <br /> These findings highlight the therapeutic potential of miRNAs in both in vivo and in vitro models and suggest further exploration of their role in neuroprotection and cone photoreceptor development.