Retinal Damage and Regeneration in the African Spiny Mouse (Acomys Dimidiatus): a Novel Mammalian Model for Translational Research

The loss of sight that results from diseases like retinitis pigmentosa (RP) and macular degeneration is especially devastating because it is currently irreversible. Therapeutic strategies such as gene therapy and cell-based transplantation hold great potential, but are only an option for a small group of patients, and several technical and theoretical challenges must be overcome before they become widely available. One complementary approach to treating retinal degenerative diseases is to find ways to promote endogenous regeneration in the diseased or damaged retina. Across the animal kingdom, several vertebrate species, including fish, amphibians, and reptiles, are capable of regenerating their retinal neurons in response to acute injury. Research into the mechanisms regulating retinal regeneration in these species has provided valuable information and highlighted the critical role of retinal M‹ ller glia as the source of regenerating cells. However, to translate these findings into therapies, it would be helpful to incorporate an animal model that more closely mirrors human ocular physiology to probe the regenerative potential of the mammalian retina. In recent years, spiny mice (Acomys) have become the focus of intense research for their ability to heal skin wounds without scars. Further studies have revealed that spiny mice exhibit regenerative capacity beyond the skin, in tissues such as the heart and the spinal cord. This raises the question of whether these mammals can regenerate retinal neurons in response to damage. Our recent studies have shown that the spiny mouse exhibits a pro-regenerative response to acute retinal damage, which is characterized by M‹ ller glia and microglial proliferation, concurrent with a lack of the reactive gliosis that is observed in the non-regenerating Mus musculus retina following damage. Importantly, following acute retinal damage that causes extensive loss of retinal ganglion cells (RGCs), we observed a significant increase in RGC number in Acomys beginning at 21 days post injury. However, during the course of our experiments, we observed a bimodal distribution in the RGC recovery response, wherein one group of spiny mice displayed a strong RGC recovery, whereas another group displayed weak recovery (and these differences were not due to age, size, or sex). Given the well documented propensity of spiny mice to hyperglycemia and diabetes, we hypothesize that the differential RGC recovery response is due to differences in glycemic status. To test this hypothesis, we propose two specific aims: 1) we will track blood glucose levels in a cohort of spiny mice before and after retinal injury to determine whether high blood sugar is negatively correlated with the magnitude of RGC recovery, and 2) we will determine whether exogenously provided insulin can boost RGC recovery in normoglycemic and hyperglycemic spiny mice. The results of our studies may identify promising avenues for promoting regeneration in human patients with retinal degenerative diseases.