Abstract
Presentation Description :
Glaucoma is the world’s leading cause of irreversible blindness. This disease causes vision loss by damaging and ultimately killing retinal ganglion cells (RGCs), the projection neurons of the retina which communicate visual information to the brain by way of the optic nerve. While glaucomatous vision loss can be slowed or halted through reduction of intraocular pressure, clinicians currently have no treatments capable of restoring vision in glaucoma or any other optic neuropathy. This presentation will describe our laboratory’s work aimed at developing innovative regenerative medicine-based approaches to repopulating RGCs within the retina and regenerating the optic nerve in animal models of optic neuropathy. We differentiate human ES and iPS cells into RGCs and then transplant them into the eyes of mice. We have demonstrated that the spontaneous engraftment of donor human RGCs into the mature mammalian retina is highly inefficient and is blocked by the internal limiting membrane (ILM), a basement membrane that devices the neural retinal parenchyma from the vitreous cavity. Proteolytic ILM digestion or developmental induction of ILM permeability conferred by mutations in the laminin alpha-1 gene both dramatically increase the migration of donor RGCs into the neural retina and the stratification of donor RGC dendrites within the retinal inner plexiform layer, where synaptogenesis with host bipolar and amacrine cells can occur. Ongoing work is evaluating the electrophysiological integration of donor neurons in the host retinal neurocircuitry using transsynaptic circuit tracing and optical electrophysiology in mice, rats, and non-human primates. Ultimately, our findings provide a pathway towards therapeutic RGC transplantation which could yield vision restorative treatments for human patients with optic neuropathy.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.