When something breaks, you want to fix it. And when you fix the item in question, you want it to stay fixed and not keep breaking. It’s even better to find out why something is breaking so that you can fix it once and for all.
The same can be said about our bodies—particularly our eyes. Two eye diseases, age-related macular degeneration and retinitis pigmentosa, have limited treatments. Still, research is taking place to learn what goes wrong in these diseases and how to possibly fix things at the genetic level to improve vision.
A group of researchers at the University of California Irvine, found that DNA damage in the retina contributes to age-related macular degeneration. By targeting specific types of retina cells, they develop treatments that slow or stop disease progression.
Since the retina is both exposed to light and has high metabolic activity, it is susceptible to oxidative stress and the build-up of DNA damage over time—factors linked to aging. Researchers compared a mouse model of young, healthy mice to naturally aging mice with reduced levels of a DNA repair enzyme, ERCC1-XPF. By three months of age, the aging mice showed signs visual impairment, alterations in the retina, abnormal blood vessel formation, changes in gene expression and mitochondrial dysfunction in the retinal pigment epithelium. These changes are similar to those observed in the human eye during aging.
The hope is that the more that is known about how DNA damage leads to eye diseases such as age-related macular degeneration, the better researchers can develop treatments to address the causes of vision loss. This could include strategies to offset oxidative stress, enhance DNA repair, or remove damaged cells before they cause harm.
“We plan to investigate which cell types drive age-related changes by selectively impairing DNA mechanisms,” said co-corresponding author Dorota Skowronska-Krawczyk, UC Irvine associate professor of physiology and biophysics. “Our goal is to advance the development of preventative interventions that significantly reduce the burden of age-related vision loss and improve the quality of life for millions.”
When it comes to retinitis pigmentosa, research using CRISPR gene editing shows potential in correcting the mutation that causes the disease. Work also done at University of California Irvine, in collaboration with the Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard used the gene-editing tool to correct a mutation in a mouse model of the disease. They were able to restore production of rhodopsin, a sensory protein needed for vision. Use of the CRISPR tool also led to improvements in the structure and function of the retina.
While there are treatments that can help manage the disease, there is no cure. The idea that CRISPR can correct a mutation is what makes this research so promising. Rhodopsin plays an important structural role in the rod photoreceptors. Mutations in the genetic instructions for making rhodopsin damages the structure and function of these cells, leading to their death and resulting in vision loss.
Scientists used the CRISPR-Cas9 tool known as base editing. This is a gene editing strategy that allows for the precise targeting and replacing of specific DNA sequences. With this tool, they edited a rhodopsin-150K mutation in a mouse model of retinitis pigmentosa. In humans, this mutation causes a rare autosomal recessive form of disease, which is inherited by a child who gets the mutated gene from both parents.
The gene editing strategy edited 44 percent of the rhodopsin gene product in the treated mice. In comparison with the untreated mice, the ones treated within 15 days of birth, had modest improvements in retinal function. Mice treated after 15 days had retinas that were too damaged to be repaired by gene editing. Researchers are optimistic that they can get a greater improvement in retinal function by enhancing the dosing and improving the surgical technique, since the treatment was uneven throughout the retina.
Another promising finding was that the gene editing treatment prevented the loss of retinal tissue layer called the outer nuclear layer. This layer has the nuclei of rod and cone photoreceptors. Saving the rod photoreceptors is expected to support the health and function of cone photoreceptors, since rods play a critical role in maintaining cones.
Both of these research projects demonstrate how fixing problems at the genetic level may lead to improved outcomes for those who have age-related macular degeneration and retinitis pigmentosa. While more work is needed, these studies give a glimpse what can be done in the future to preserve and potentially improve vision.