Development of Optic Nerve Relays to Restore Retinofugal Connections

Project Summary/Abstract Optic neuropathies and retinal diseases are leading causes of irreversible blindness worldwide. Currently, there are no therapies to restore vision loss. Whole eye transplants could restore vision if the neural circuits between the eye and the brain could be restored. The long-term goal of this proposal is to develop therapies

that regenerate lost retinofugal pathways and enable whole eye transplants. In experimental models of central nervous system injury, neural stem cells (NSCs) have been used to form neuronal relays that restore injured connections and function. Preliminary data suggests that NSCs similarly integrate with the injured visual

system. The central hypothesis is that stem cell-derived neurons transplanted into the optic nerve can restore function by receiving inputs from the eye and extending long-distance axonal projections. This proposal will test this hypothesis by pursuing the following specific aims: 1) identify the optimal donor cell type to establish

optic nerve relays, 2) optimize survival of host RGCs using gene editing in conjunction with an optic nerve relay, and 3) evaluate the degree to which optic nerve relays adjacent to terminal targets form synapses. The proposed studies are significant because they develop a novel use of stem cells to form neuronal relays to

achieve robust, long-distance axonal regeneration and enable whole eye transplants. The positive translational impact is the potential development of therapeutic strategies that restore vision, including whole-eye transplants. This K08 grant will allow Dr. Jiun Do, M.D., Ph.D. to obtain the scientific training and professional skills to

establish a research program focused on optic nerve regeneration and become an independent investigator. To facilitate achieving this goal, Dr. Do has assembled an exceptional mentoring team at UCSD consisting of Dr. Mark Tuszynski, M.D., Ph.D., an expert in neuroregeneration and neural stem cell therapies in the spinal

cord, and Dr. Derek Welsbie, M.D., Ph.D., an expert on retinal ganglion cell degeneration and neuroprotection. This is complemented by an external clinician-scientist committee that includes Drs. Zhigang He, Ph.D. and. Larry Benowitz, Ph.D., experts in optic nerve regeneration and successful scientists in vision research. Key

components of this training plan include: 1) acquisition of scientific and technical expertise to develop stem cell technologies and modify the visual system, 2) formal didactic courses and training in grant writing, ethics, stem cell biology, and gene editing, 3) generation of data for an R01 submission, and 4) planned transition to

independence through mentorship. This work takes place at UCSD, an outstanding research environment and world class facility, and in the Department of Ophthalmology, which has a strong track record of producing successful clinician-scientists. Combined with his clinical training in glaucoma, this career development plan

will allow Dr. Do to become a leading clinician-scientist with an independent R01-funded research program focused on developing therapies for optic nerve regeneration, eye transplantation, and vision restoration.