Commonalities in late stages of inherited blinding diseases suggest targets for therapy

December 20, 2017, University of Pennsylvania
Commonalities in late stages of inherited blinding diseases suggest targets for therapy
A heat map showing patterns of gene expression reveals similarities between two different forms of retinitis pigmentosa, a blinding disease. The commonalities involve innate immune pathways, and point to new strategies for treatment. Credit: University of Pennsylvania

Gene therapy holds promise for treating a variety of diseases, including some inherited blinding conditions. But for a gene therapy to be effective, one must know the precise gene responsible for a given individual's disorder and develop a tailored treatment. For diseases that may be caused by mutations in many different genes, developing individual gene therapy approaches can be prohibitively costly and time-intensive to pursue.

In a new study published in the journal Scientific Reports, a research team from the University of Pennsylvania School of Veterinary Medicine took a different approach, using canine models of vision-robbing disorders. Rather than looking at what distinguished two forms of , or RP, a progressive blinding disease, they looked for what they had in common: specifically, what genes were expressed at the later stages of disease. Their findings, showing the involvement of common immunity-related pathways, point toward potential new strategies for treating the late stages of inherited blinding diseases.

"We were surprised to find so many similarities between these two diseases, but most striking was that some of these common signatures are shared with other conditions like diabetic retinopathy and ," said William A. Beltran, senior author on the study, an associate professor of ophthalmology in Penn Vet's Department of Clinical Sciences and Advanced Medicine and director of the Division of Experimental Retinal Therapies. "If we could perhaps modulate these pathways and prolong survival of photoreceptor cells, we might be able to delay any further degeneration even when intervening at these later stages of disease."

Beltran co-authored the work along with first author Raghavi Sudharsan, a research associate in his lab; Daniel P. Beiting, assistant professor; and Gustavo D. Aguirre, professor of medical genetics and ophthalmology.

Retinitis pigmentosa is a progressive form of blindness that affects approximately 1 in 4,000 people. Mutations in at least 60 genes are known to cause the disease, and many people are not diagnosed until after a a substantial proportion of photoreceptor cells, the eye's rods and cones, have already degenerated and died.

"One of the major limitations in developing a corrective is that it will treat only a single disease," said Sudharsan. "We wanted to identify some potential therapeutic targets that are common not just to one but to multiple forms of retinitis pigmentosa at late-stage disease, when it is more likely to be clinically diagnosed in a patient population."

With that in mind, the Penn Vet team chose to examine two of their well-established canine models of RP, which recapitulate many features of the human diseases, each involving mutations in different genes. Their goal was to determine what were playing a role in cell death during the later stages of degeneration.

To do so, they examined two canine models of RP, rcd1 and xlpra2. Both involve rapidly progressing blindness. Analyzing retinas at a point when more than 50 percent of the photoreceptor cells had died, the team performed transcriptomic analysis to find out what genes were activated at this late stage compared to gene expression in the retinas of normal dogs.

Their results showed that both forms of RP had clear differences in gene expression compared to normal retinas. Using a software program to identify patterns in the genes that were activated, they found that several pathways stood out as being activated in both diseases, including the complement pathway, the inflammasome pathway and the Toll-like receptor signaling pathway. These three and others are components of innate immunity, the arm of the immune system that responds both to invading pathogens and to the body's own cells when they are damaged or dying, helping clear away debris.

Though the results make clear that innate immunity and inflammation are involved in the advanced stages of rcd1 and xlpra2, the researchers cannot be sure whether the molecular pathways at work are trying to clean up the mess caused by the degenerating photoreceptor cells, or whether they are part of the problem, a sort of hyperactive immunity causing damage in its own right.

"We see upregulated that are related to inflammation," Sudharsan said. "As to which are helpful and which are further exacerbating the degeneration, we can't answer at this stage; we need to study this further."

An unexpected finding was that many of the innate immunity pathways that were active in the late stages of these inherited blinding diseases were the same as those that are associated with more common vision disorders including diabetic retinopathy and age-related macular degeneration, or AMD. Because there are already drugs in development for treating those diseases, these findings hint that these same compounds might also be able to address the degeneration occurring in RP.

In addition, the researchers noted, there are no large animal models for age-related macular degeneration that faithfully replicate features of the human condition. The similarities between this common condition and the current findings in late-stage RP suggest that the canine RP models could serve as stand-ins to evaluate the effectiveness of pharmaceutical interventions that target innate immunity pathways in AMD

Despite this new direction for identifying targets for pharmaceutical interventions against RP, the researchers underscore that gene therapy still has great potential and possible benefits, and they are actively pursuing efforts with this approach for several forms of RP. But therapies that target common molecular pathways active late in disease could be part of a multi-pronged treatment plan for people with these inherited conditions.

"It could be that a cocktail of therapies will eventually be used in these cases," Beltran said.

"These approaches," said Sudharsan, "may help sustain for the time period needed to develop a specific gene therapy."

Explore further: Same cell death pathway involved in three forms of blindness

More information: Raghavi Sudharsan et al, Involvement of Innate Immune System in Late Stages of Inherited Photoreceptor Degeneration, Scientific Reports (2017). DOI: 10.1038/s41598-017-18236-7

Related Stories

Same cell death pathway involved in three forms of blindness

January 16, 2014
Gene therapies developed by University of Pennsylvania School of Veterinary Medicine researchers have worked to correct different forms of blindness. While effective, the downside to these approaches to vision rescue is that ...

Before retinal cells die, they regenerate, vet blindness study finds

March 18, 2016
Until relatively recently, the dogma in neuroscience was that neurons, including the eye's photoreceptor cells, rods and cones, do not regenerate. This is the reason that nerve damage is thought to be so grave. More recent ...

Study stops vision loss in late-stage canine X-linked retinitis pigmentosa

October 12, 2015
Three years ago, a team from the University of Pennsylvania announced that they had cured X-linked retinitis pigmentosa, a blinding retinal disease, in dogs. Now they've shown that they can cure the canine disease over the ...

New model for hard-to-study form of blindness paves way for future research

September 6, 2017
Macular degeneration is the leading cause of vision loss in older adults, but scientists have long struggled to study and replicate key elements of the disease in the lab. A study published in the Proceedings of the National ...

Genetic treatment for blindness may soon be reality

November 11, 2017
Patients who had lost their sight to an inherited retinal disease could see well enough to navigate a maze after being treated with a new gene therapy, according to research presented today at AAO 2017, the 121st Annual Meeting ...

Researchers identify treatment target for blinding diseases

September 28, 2016
New research published in Cell Reports identifies a potential treatment target for blinding diseases such as retinitis pigmentosa and advanced dry age-related macular degeneration. In the study, researchers at Washington ...

Recommended for you

Satellite imaging techniques may help reduce preventable vision loss

May 11, 2018
By adapting pattern recognition techniques used to assess satellite images, scientists have devised a novel way to diagnose blinding eye diseases, such as age-related macular degeneration.

Ophthalmologists link immunotherapy with a serious eye condition

May 7, 2018
New immunotherapy treatments offer a remarkable chance for survival for patients with advanced melanoma and hard-to-treat cancers of the bladder, kidney and lung.

Burnout, depression can affect ophthalmology residents, study finds

May 4, 2018
A new study led by Brown University researchers finds that ophthalmology residents across the U.S. face a substantial burden of burnout and depression, which may affect not only the residents themselves but also the quality ...

AI better than most human experts at detecting cause of preemie blindness

May 3, 2018
An algorithm that uses artificial intelligence can automatically and more accurately diagnose a potentially devastating cause of childhood blindness than most expert physicians, a paper published in JAMA Ophthalmology suggests.

New diagnostic technique picks up the S in vision

May 1, 2018
A new technique that could help improve diagnosis of vision disorders has been successfully tested at the University of Bradford, UK.

A bit of dark chocolate might sweeten your vision

April 26, 2018
It may not replace prescription glasses, but a few bites of dark chocolate might offer a slight and temporary bump up in vision quality, new research suggests.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.