In medical circles, the eyes are considered the front of the brain, and it is the interaction between the eyes and the brain that is responsible for vision. When something isn’t working correctly in either the eyes or the brain, vision is impaired. What are the brain circuits responsible for visual acuity? Also, is there a way to restore vision lost due to inherited retinal diseases? Research is working to provide answers to these questions.
Scientists at UC Irvine School of Medicine, along with collaborators at Helmholtz Munich Research Institute in Germany, developed a new virus-like particle (VLP) to enhance the editing of proteins that cause inherited diseases. This system is called Engineered Nucleocytosolic Vehicles for Loading of Programmable Editors (ENVLPE) and it corrected two mutations associated with blindness.
By utilizing RNA-protein interactions, the VLPs were modified to be more efficient. An important advantage of this system is that any CRISPR system can be put into the ENVLPE with no complicated cloning. Researchers at Helmholtz Munich tested the ENVLPE VLPs in various CRISPR models, such as gene knockout, homology-directed repair, base editing and CRISPR-activation assays. The Helmholtz Munich team also applied the VLPs in different cell types including workhouse tissue culture lines, brain organoids and primary T cells.
When it came time to test VLPs in a live animal, the UC Irvine team took over since they had the expertise in visual physiology and ocular surgery. They showed that a single injection of the ENVLPE VLPs into mouse models with inherited retinal degeneration corrected the mutations. This led to restored protein productions and, of course, vision.
“We are excited to further test the ENVLPE system and investigate new models that can be treated with these VLPs,” says Krzysztof Palczewski, PhD, the lead researcher and the Irving H. Leopold Chair, Donald Bren & Distinguished Professor, Ophthalmology & Visual Sciences at UC Irvine. “We also hope to develop more advanced purification and characterization pipelines, moving these promising biologics closer to the clinic and developing new therapies for diseases.”
Still, the question remains: Which brain circuits are responsible for visual acuity and can this help with the development of vision restoration therapies? A study at National Institutes of Health (NIH) identified which brain circuits are responsible for visual acuity and how damaged retinal cells affect them.
While there has been progress in repairing the eye, little attention has been given to the downstream brain circuits. Researchers wanted to learn if these brain circuits lose functionality when there are changes to the retinal inputs. In particular, they wanted to know how the neurons downstream of the retina are affected by damage to the retinal ganglion cells (RGCs).
RGCs receive signals from other retinal cells and send them to the brain. They connect to neurons in a relay center in the brain called the lateral geniculate nucleus (LGN), which sends signals to the visual cortex. The study looked at two kinds of LGN cells that respond to different types of visual information and form parallel processing pathways: X-LGN neurons (visual acuity) and Y-LGN neurons (motion perception).
Scientists examined the effects of retinal cell loss on the X and Y pathways using an animal model. After an injury to the RGCs in the retina, recording of LGN neuronal responses were done to study the impact on the X and Y pathways. It was discovered that the X-LGN neurons didn’t respond appropriately to visual stimuli. Conversely, the Y-LGN neuron responses remained intact. This suggests that retinal cell loss affects the downstream pathways in different ways. In particular the X pathway is most affected, while the Y pathway remains largely unaffected.
These findings suggest that vision restoration therapies may need to target both the retinal cells and the brain circuits responsible for visual acuity. Future studies aim to further understand the changes in visual perception that occur during retinal cell loss.
These advances underscore the importance of addressing vision loss as both a retinal and neurological challenge. Breakthroughs in retinal gene editing, combined with deeper insight into the brain circuits that govern visual acuity, suggest a more holistic approach to treating vision loss. By repairing damaged retinal cells while preserving or restoring downstream neural pathways, scientists are paving the way for therapies that could meaningfully improve visual function and quality of life for patients with inherited retinal diseases.