Johns Hopkins School of Medicine

Restoring Vision through Regenerative Medicine

Our sense of vision is critical to interacting with the world around us. Diseases that cause vision loss or blindness reduce quality of life, psychological wellness, and financial wellbeing while increasing social isolation, injuries, and healthcare costs. Optic neuropathies are a class of neurodegenerative diseases that cause irreversible blindness by impairing transmission of visual signals from the eye to the brain. Retinal ganglion cells (RGCs), the tertiary retinal projection neurons, are selectively lost in optic neuropathies, and since mammals do not spontaneously regenerate these CNS neurons, there are no treatments capable of restoring lost vision in patients suffering from optic neuropathies. As a glaucoma specialist, Dr. Johnson clinically manages some of the world's >80 million patients afflicted with the disease.

The Johnson laboratory is developing regenerative medicine-based treatment strategies to restore lost vision in patients suffering from optic neuropathy, through transplantation of stem cell-derived RGCs. Using in vivo models of glaucoma, traumatic optic neuropathy, and ischemic optic neuropathy (among others) we are exploring the molecular mechanisms thatunderlying structural engraftment and functional circuit integration between human donor neurons and the diseased anterior visual pathway. 

Our work has been enabled by our discovery that the retinal internal limiting membrane (ILM), a basement membrane which separates the retinal parenchyma from the vitreous cavity, obstructs the engraftment of donor neurons into the retina. Leveraging several innovative methods to disrupt the ILM enzymatically, developmentally, and mechanically, we have recently demonstrated that donor RGCs are capable of functionally integrating into light sensitive retinal circuits. 

Ongoing projects in the lab aim to 1) enhance the long-term resilience of donor neurons to ensure survivability over the lifetime of the recipient; 2) augment and tune the specific inner retinal circuits into which donor RGCs integrate based on their subtype specificity; and 3) achieve long-distance guidance and growth of RGC axons to key subcortical visual centers in the brain. We leverage a number of sophisticated techniques to promote these outcomes, including: genetic engineering of human pluripotent stem cells and retinal organoids; delivery of genes and drugs through nanoparticle vehicles; 2-photon calcium imaging combined with visible light stimulation of the retina ex vivo and in vivo; transsynaptic circuit tracing; tissue clearance and light sheet microscopy; and single cell and spatial multiomics. In addition, we are developing clinically translatable, novel surgical approaches and biomedicalengineered tools to enable the transplantation of new donor RGCs into human patients.