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Detecting & Fixing Eye Diseases

Posted by Ilena Di Toro | Posted on January 24, 2023

In eye diseases like retinitis pigmentosa, age-related macular degeneration and Leber congenital amaurosis, things are going on in the cellular level that occur before anything is detected by way of a test or observation. It would be great if these changes could be detected sooner and if there was a way to stop the deterioration at the cellular level. Well, research is taking place to study these very things.

Detecting Cellular Events
The lab of Anand Swaroop, Ph.D., senior investigator and chief of the National Eye Institute (NEI) Neurobiology Neurodegeneration and Repair Laboratory, part of the National Institutes of Health (NIH) has been able to detect changes in rod photoreceptors in the mouse model of retinal degeneration several days before these changes are observable. This could lead to new therapeutic targets for retinitis pigmentosa and age-related macular degeneration.

Researchers used the mouse model Pde6b d1/rd1 and they found that cell structural changes were apparent as early as postnatal day 10. The mouse model had a shortening of the rod photoreceptors’ outer segments, which is the region where the vision starts. Also, the outer nuclear layer of the rod became thinner. Earlier studies focused on disease progression at or after rod death (after postnatal day 10), the profiling of rod at days 2 through 6 shows specific abnormalities in the expression of genes associated with the mitochondria and metabolism.

The way the gene expresses itself suggested that the photoreceptor didn’t have a normal development, despite having a normal appearance. At postnatal day 6, high levels of mitochondrial stress were evident before there were signs of structural and functional degeneration. This research showed that both enhanced mitochondrial turnover and defects in the calcium-regulated proteins, which is a sensor of intracellular calcium levels. This points to metabolic imbalance and mitochondrial abnormalities being related to calcium signaling that comes before rod death. It suggested that reducing calcium levels by way of drug therapy might be one way to slow down retinal degeneration.

Maintaining Vision Once the Damage is Done
What happens once the retina started deteriorating? Is it possible to fix the damage and maintain vision? Research at the University of California Irvine (UCI) School of Medicine demonstrate that just might be possible.

Work in the lab of Krzysztof Palczewski, PhD, the Donald Bren Professor of Ophthalmology at the UCI School of Medicine, shows that base editing, which is the introduction of point mutations in DNA without making double-stranded DNA breaks, may lead to long lasting protection for the retina and prevent deterioration in persons with inherited retinal degeneration, such as Leber congenital amaurosis.

Persons with Leber congenital amaurosis that have the RPE65 mutation have accelerated cone photoreceptor dysfunction and death. As a result, they experience early visual impairment. So, it was key to develop a treatment that both compensates for lost RPE65 function and protects photoreceptors from further damage.

Scientists did base editing in rd12 mice and they found that it was able to maintain the function and survival of the cone photoreceptors on a long-term basis.

“Protecting photoreceptors is key to preventing further deterioration of vision in Leber congenital amaurosis patients, which means this discovery could lay the foundation for establishing the therapeutic potential of base editing as a one-time, durable treatment,” said Palczewski. Researchers hope to do preclinical testing in primates before moving on to possible a clinical trial on humans.

No one wants to develop retinitis pigmentosa, age-related macular degeneration or Leber congenital amaurosis, thanks to research, blindness as a result of these diseases is less likely to happen.


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