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. 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 Müller 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 an increase in RGC number in Acomys beginning at 21 days post injury, and by four months post injury RGCs were significantly more abundant than at 4 dpi, indicating a remarkable recovery from damage. We hypothesize that the new RGCs are descendants of the proliferating Müller glia, however we currently lack the genetic tools needed to accurately trace the lineage of the recovered RGCs. Accordingly, we propose two specific aims: 1) We will use AAV vectors to mediate fluorescent reporter gene delivery to Acomys Müller glia. We will use the Müller glia specific ShH10 AAV vector in tandem with Müller glia specific promoters to drive inducible expression of GFP or RFP in these cells following intravitreal injection. We will then be able to track the fate of the proliferating Müller glia in the Acomys retina after injury. 2) Using AAV-mediated fluorescent reporter gene delivery, we will isolate the labeled Müller glia by flow cytometry from control and injured retinas at various tiempoints, and will perform RNA sequencing on the isolated cells. These data will help us determine the gene expression programs and signaling pathways specifically in Müller glia that mediate the regenerative response to injury in the Acomys retina. Overall, the results of our studies may identify promising avenues for promoting regeneration in human patients with retinal degenerative diseases.