RGC Transplantation as a Treatment for TBI-Related Optic Nerve Injury
Abstract
Ocular injuries account for up to 13% of all injuries sustained by Soldiers in present-day warfare. These injuries cost the United States economy $25 billion in health care, work lost, and family support. More importantly, these injuries impact the vision and quality of life of Soldiers, Veterans, and their Families. Blast injury can cause damage to the optic nerve, the telephone cable that carries visual information from the eye to the brain. The nerve cells that carry information in the optic nerve are called retinal ganglion cells (RGCs). Blast-induced injury to the optic nerve and resulting death of RGCs can cause vision loss. Since the eye does not have the ability to regenerate or significantly replace lost RGCs, restoring lost vision to our Soldiers and Veterans suffering from optic nerve damage is, unfortunately, not possible. However, there is increasing hope that replacing such lost vision may be possible in the foreseeable future. Research strategies that are being developed include prosthetic retinal implants, reactivation of intrinsic regeneration mechanisms, whole eye replacement, and RGC transplantation for optic nerve regeneration. The latter approach, optic nerve regeneration, has become closer to a feasible reality in recent years due to developments in axon regeneration and stem cell biology, with new techniques permitting the differentiation of human pluripotent stem cells into RGCs for cell replacement therapy. Cell replacement in the retina holds great promise for restoring lost sight. In an attempt to restore RGCs and visual function lost secondary to optic nerve injury and disease, we and others have been working to replace lost cells by transplantation of stem cell-derived RGCs. Our ongoing experiments have shown partial survival of grafted cells in healthy and damaged retinas following transplantation of RGCs in animal models. However, as promising as these studies are, there are still major challenges that need to be addressed. Among the challenges are that transplanted RGCs often do not survive well in their new hosts, and the cells that do survive the initial transplantation tend to die over time. An additional and deeper challenge is that we need to develop better methods to help the fibers growing from the RGCs (which are called axons) find their way to the correct sites in the brain. And once the axons arrive in the brain, we need to find ways to help them form functional connections (which are called synapses) to the right cells in the brain. In the work described in this application we propose to employ a collaborative team-based approach with investigators experienced in the study of optic nerve injury and regeneration to simultaneously address these and other challenges in our continuing efforts to help patients regain lost vision by means of RGC transplantation-based optic nerve regeneration. In the proposed studies we will optimize the generation of RGCs from human stem cells, explore the role of intrinsic and extrinsic factors in RGC survival and integration, develop improved methods to get transplanted cells integrated into the retina, explore how microenvironmental factors influence RGC survival, and test these improvements using mouse and large animal (pig) models of traumatic optic neuropathy. These complementary efforts, taken together, will, hopefully, help advance the field and get us closer to the point where the dream of restoration of lost vision by optic nerve regeneration transitions from a dream to a reality.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310589
Entities
People
- Donald Zack
Organizations
- Johns Hopkins University
- United States Army