Vision Restoration For Optic Neuropathy

RGC replacement milestones, which have been partly achieved in isolation.

(1) Develop a reliable source of transplantable RGCs. (2) Deliver donor cells (red) safely. (3) Promote long-term donor RGC survival in the recipient eye. (4) Establish retinal localization and neuritogenesis. (5) Form synaptic connectivity with host retinal interneurons in the inner plexiform layer. (6) Conduct light-evoked, photoreceptor-transduced signals within the visual pathway. (7) Achieve axon growth toward the optic nerve head and into the optic nerve. (8) Develop myelination of new axons. (9) Reinnervate retinorecipient nuclei, including suprachiasmatic nucleus, lateral geniculate nucleus, olivary pretectal nucleus, and superior colliculus. Reprinted from: Zhang KY, Aguzzi EA, and Johnson TV. Retinal ganglion cell transplantation: Approaches for overcoming challenges to functional integration. 2021. Cells. 10(6):1426.

The Johnson Laboratory at the Johns Hopkins Wilmer Eye Institute

Vision restoration through regenerative medicine: RGC replacement

To restore vision in optic nerve diseases, RGCs need to be replaced. This means not only repopulating new RGCs within the retina, but also ensuring that they regenerate their proper communication stations (synapses) with bipolar and amacrine cells in the retina and grow lengthy axons into the parts of the brain that are important for receiving and processing visual information. The numerous challenges that exist to functional RGC replacement are shown in the figure, and amount to no small task. RGC replacement has been theorized for decades, but due to the complexity of the problem, has been largely relegated to “science fiction”. However, the past decade has witness unprecedented scientific developments in stem cell biology and cellular neuroscience, such that the tools necessary restore vision in optic nerve diseases exist. Vision restoration in optic neuropathy is now a “scientific possibility”.

The Johnson Laboratory leverages cutting edge molecular biology, neuroscience, and imaging tools to study all aspects of the optic nerve regeneration process. We collaborate closely with Dr. Don Zack’s laboratory, who have developed innovative tools allowing us to differentiate RGCs from human stem cells. Working with these donor RGCs, we study survival, migration, and engraftment following transplantation in multiple optic nerve disease models. We use advanced microscopy techniques to study RGCs over time in tissue and in living eyes and we use optical electrophysiology and transsynaptic tracing to study the functional communication of donor RGCs with other neurons within the visual pathway. We collaborate with top scientists from all over the world through the RGC Repopulation, Stem Cell Transplantation, and Optic Nerve Regeneration (RReSTORe) Consortium, and aim to contribute to future treatments capable of reversing blindness in patients with optic neuropathy.

RGC replacement milestones, which have been partly achieved in isolation. (1) Develop a reliable source of transplantable RGCs. (2) Deliver donor cells (red) safely. (3) Promote long-term donor RGC survival in the recipient eye. (4) Establish retinal localization and neuritogenesis. (5) Form synaptic connectivity with host retinal interneurons in the inner plexiform layer. (6) Conduct light-evoked, photoreceptor-transduced signals within the visual pathway. (7) Achieve axon growth toward the optic nerve head and into the optic nerve. (8) Develop myelination of new axons. (9) Reinnervate retinorecipient nuclei, including suprachiasmatic nucleus, lateral geniculate nucleus, olivary pretectal nucleus, and superior colliculus. Reprinted from: Zhang KY, Aguzzi EA, and Johnson TV. Retinal ganglion cell transplantation: Approaches for overcoming challenges to functional integration. 2021. Cells. 10(6):1426.

The video above shows a 3D reconstruction of retinal tissue into which human stem cell derived RGCs (red) have been transplanted. The recipient retina is labeled in blue and demonstrates the well-organized layered architecture of the retinal tissue. Five RGCs are present in this area of tissue, but only the one in the center has integrated into the retina, which was enabled through digestion of the internal limiting membrane on the surface of the retina. The video demonstrates computational tracing of the integrated RGC and its dendrites. Rotation of the tissue shows that the integrated RGC has elaborated dendrites within the inner plexiform layer (the acellular layer between the RGC layer and the inner nuclear layer) where synaptogenesis with bipolar cells can occur.