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

The progressive loss of sight that results from diseases like retinitis pigmentosa (RP) and macular degeneration is especially devastating because it is currently irreversible. Breakthrough therapeutic strategies such as gene therapy and cell-based transplantation are on the horizon, but gene therapy is only an option for a small group of patients, and several technical and theoretical challenges must be overcome before cell transplantation becomes a viable strategy. 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 yielded valuable information and highlighted the critical role of retinal Muller 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 complex musculoskeletal tissue regeneration and possess cytoprotective mechanisms that limit tissue damage to the heart and spinal cord. This raises the question of whether these mammals might regenerate retinal neurons in response to damage, or whether they can resist damage to preserve retinal function. We have obtained exciting preliminary data that the former may indeed be the case. To further explore this question, we propose in this pilot study to rigorously test the hypothesis that the spiny mouse possesses the capacity to regenerate retinal neurons in response to damage, and to take the first steps in determining the underlying biological mechanism. To do this, we propose three specific aims: 1) we will monitor cell death, cell proliferation, and cell differentiation in the spiny mouse retina in response to ablation of inner retinal neurons; we will compare this response to that of outbred laboratory mice (Mus musculus) which are not capable of retinal regeneration; 2) we will use a high energy laser to ablate the retinal photoreceptors in Acomys and Mus retinas, and will examine the same responses as in Aim 1; and 3) we will employ single-cell RNA-Sequencing (scRNA-Seq) at several time points over the course of two weeks following damage to characterize how subtle differences in cellular phenotypes regulate the different repair outcomes in Acomys vs. Mus retinas. We will then compare our scRNA-seq data with previously published datasets from animal models that are capable of full retinal regeneration, which will allow us to identify common and distinct mechanisms of retinal repair and regeneration in the mammalian retina. This study will be the first of its kind to document the natural regenerative potential of any mammalian retina and may identify promising avenues for promoting regeneration in human patients with retinal degenerative diseases.