New studies in rats suggest the drug reserpine, approved in 1955 for high blood pressure, might treat the blinding disease retinitis pigmentosa. No therapy exists for this rare inherited disease, which starts affecting vision from childhood. A report on the studies, conducted at the National Institutes of Health (NIH), published today in eLife.
"The discovery of reserpine's effectiveness may greatly speed therapeutics for retinitis pigmentosa and many other inherited retinal dystrophies, which can be caused by one of more than a thousand possible mutations affecting more than 100 genes. Reserpine's neuroprotective effect is independent of any specific underlying gene mutation," said the study's lead investigator, Anand Swaroop, Ph.D., senior investigator at NIH's National Eye Institute.
Inherited retinal dystrophies cause degeneration of the retina, the light-sensing tissue at the back of the eye. Vision loss can be present at birth or develop later in early adulthood. Disease progression varies depending on the gene involved. Some genetic defects may be inherited as dominant, where a mutation in just one of the two copies of the gene (one each from the mother and father) is sufficient to cause vision loss. Other genetic defects are recessive, where both copies of a gene must carry a mutation to cause vision loss. Gene therapies to correct inherited retinal dystrophies are promising, but take a long time to develop, are gene specific, and are often quite expensive.
The findings are the latest evidence that reserpine improves survival of photoreceptor cells, the light-detecting retinal neurons that die in retinitis pigmentosa and other retinal dystrophies. In 2023, the Swaroop Lab demonstrated reserpine's potential for preventing vision loss from LCA10 , a retinal dystrophy caused by mutations in the CEP290 gene.
In its latest work, Swaroop's team tested reserpine in a rat model of a dominant form of retinitis pigmentosa caused by a mutation in the visual pigment gene rhodopsin. This disease mutation is common in Irish Americans with retinitis pigmentosa. Compared to untreated rats, reserpine preserved the process by which photoreceptors convert light that enters the eye into electrical signals that are sent to the brain to produce vision, known as phototransduction, in retinal cells called rod photoreceptors. Rod photoreceptors enable low-light vision; cone photoreceptors enable color vision in bright light.
Unexpectedly, reserpine better protected rod photoreceptors in female rats compared to males. The scientists also observed significant preservation of cone photoreceptors in female rats compared to male rats.
"We can only speculate about these sex-specific differences. However, future research would benefit from teasing out these differences and understanding them to lay a foundation for personalized approaches to retinal disease therapy," Swaroop said.
Swaroop's lab is developing additional, and more potent reserpine-related drugs. The idea would be to use such options to treat late-onset or slowly progressing inherited retinal dystrophies or to simply stall vision loss in aggressive retinitis pigmentosa varieties until more effective treatments are developed that can reverse that vision loss.
Reserpine is no longer used for treating high blood pressure because of its side effects. The required dosage for treating retinal degeneration, however, would be very low and directly delivered in the eye. Reserpine is a small molecule therapy, which makes it easy to deliver to target tissues in the eye.
This work was supported by the NEI Intramural Research Program.
