A Shot in the Dark: Searching for Therapies to Treat Retinitis Pigmentosa

Published on: 

An entire population gradually loses their vision, impeding everyday activities like driving in the dark, while investigators explore gene therapies in a race against the clock.

It’s night. You woke up and need to see—maybe to navigate out of your bed, to avoid the corners and ends of your furniture, to grasp the doorknob and open it out into your hallway, your bathroom, wherever you need to go.

For the average person, that sensation of small glimpses of moonlight through the blinds or a hallway lamplight glowing underneath the door growing to illuminate the shadows of a dark room takes only moments to occur. The ability to visually adjust to the darkness or benefit from a light source is regularly taken for granted, especially because it may never be known by patients with retinitis pigmentosa.

A group of rare eye diseases, retinitis pigmentosa changes how the retina responds to light as photoreceptor cells break down slowly over time. The most common early symptom of the chronic disease is nyctalopia, or the loss of night vision, and it can often begin at a young age.

“I’ve had patients tell me as a teenager, they would find great difficulty moving about in the house at night when they had to go to the bathroom in the dark, or when they go to a dimly lit restaurant or the inside of a movie theater,” Mandeep Singh, MD, Andreas C. Dracopoulos Professor of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, told HCPLive. “Those dimly lit environments are a terrible challenge for people with RP.”

Approximately 1 in every 4000 people in the United States and 1 in 5000 worldwide are affected by retinitis pigmentosa.1 The inherited retinal disease is caused by mutations in genes that play a role in the structure and function of the retina. Only a single gene therapy agent has been approved by the US Food and Drug Administration (FDA) in December 2017 to treat a severe form of retinitis pigmentosa caused by a defect in the RPE65 gene.2

As a result, the search for treatments continues, as researchers look to develop new direct therapies for other genetic subtypes and to slow the onset of this debilitating disease.

A Breakdown in Vision

Within the retina, rods and cone photoreceptors convert light into electrical signals that the brain then interprets as vision. In most forms of retinitis pigmentosa, rods in the outer portion of the retina are affected first, resulting in more concentrated vision over time. Rods are concentrated in the outer portion of the retina and primarily activated by dim light, meaning their degeneration affects peripheral and night vision.3

If the disease progresses and cones are affected, visual acuity, color perception, and central vision are impacted as well. Daytime vision will initially remain unaffected, but the loss of nighttime vision can cause disturbances with daily activities, such as driving in the dark.

Over time, the gradual narrowing of the visual fields and loss of peripheral vision can lead to patients bumping into objects in their periphery and noticing missing aspects of their vision. Later stages of the disease narrow a person’s field of vision until only some central vision remains, making it difficul to perform detailed tasks.

“It’s one of those conditions that patients live with for many years, beginning in childhood and the teens, and progression through adulthood and middle life,” Singh said. “Vision loss towards the later part of life can be pretty severe.”

A Genetic Matter

First described in 1853, the name “retinitis pigmentosa” was not attached to the disease until 1857. However, the use of the term “retinitis” is considered a misnomer, as inflammation does not play a major role in the natural progression of the disease.1

Advances in our understanding of retinitis pigmentosa has provided updated insights into its genetic underpinnings, suggesting it is caused by mutations in a gene inherited from one or both parents. The mutated gene tells photoreceptor cells to make an incorrect protein or too little or too much protein, causing cells to function improperly.

More than 100 genetic loci on 50 different genes have been linked to multiple patterns of inheritance and expression for retinitis pigmentosa. Research has shown the most common genes associated with the disease are PRPF31, PRPH2, RDH12, RHO, RPE65, ABCA4, MAK, MERTK, NR2E3, PDE6B, and RPGR.3

The condition being caused by genetic mutation could explain why many symptoms arise in childhood or early adulthood and progress over time, Singh said.

“Through decades of genetic research, we now understand that the underlying cause is genetic,” Singh said. “It’s not just 1 or 2 or 10 genes involved, but dozens of genes, upwards of 80 genes approximately, that are thought to cause retinitis pigmentosa. So, each patient with retinitis pigmentosa is carrying a mutation in one of those genes.”

Retinitis pigmentosa is made up of 2 forms: Most cases (70 – 80%) are “nonsyndromic” or involve vision loss alone and the less common “syndromic” occurs in conjunction with systemic disease. Usher syndrome is the most common form of syndromic disease, which involves both neurosensory hearing loss in addition to vision loss.1

The FDA approval of voretigene neparvovec-rzyl (Luxturna) for Leber congenital amaurosis represented an important breakthrough as the first gene therapy for a genetically defined type of inherited retinal disease on the severe end of the retinitis pigmentosa spectrum. Increased attention to genetic testing early on the disease state could aid in identifying the specific type, determine the likely course of severity over time, and help investigate new gene therapies.

“Genetic testing is really critical at this juncture in terms of finding the genetic cause of the retinitis pigmentosa,” Byron L. Lam, MD, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, told HCPLive. “But, more importantly, once you know the genetic cause, then you can determine whether patients could be included in studies.”

However, getting a diagnosis of retinitis pigmentosa can be a challenge for patients who do have access to a specialist able to diagnose the condition and uncover the underlying gene through genetic testing. Lam recommended clinicians refer patients with suspected inherited retinal disease to a specialist, who can perform genetic testing. He noted some no-cost programs exist, including from the My Retina Tracker Registry, a research database of people and families affected by rare inherited retinal degenerative diseases.

An Open Toolbox

A crucial component in treating retinitis pigmentosa is ensuring access to low vision aids and rehabilitation programs. Low vision programs, like the one offered at Johns Hopkins, provide visual assistance to patients, tools, and visual aids, and educate on techniques to improve visual function.

“I have many patients who are able to enjoy a number of vision-related activities and have achieved success in their personal and professional lives,” Singh said. “I think partnering with a low vision physician is one of the main ways to make sure that the patient with retinitis pigmentosa can enjoy their life as much as possible.”

Low vision tools can range from smartphone apps offering speech-to-text-and text-to-speech, to wearable devices that can change contrast settings and enlarge objects. Improving lighting conditions in the home, providing more light for reading, and adjusting the contrast settings on the computer can also benefit a patient.

Ultimately, however, the most important area of research remains gene therapies. A herculean task, the genetic diversity of the disease has sent labs and universities across the globe investigating various treatment strategies around the clock.

In a gene-specific approach, a specialized gene therapy using virus vectors or genome editing aims to target a specific gene. A gene-agnostic approach targets a way to treat all genes of retinitis pigmentosa or multiple at once. But the immense amount of resources required to develop even a single therapy could derail those efforts, as cost, manpower, and time become scarce resources.

“Therein lies the value of trying to develop mutation-independent treatments, because you get more bang for your buck,” Singh said. “With one medicine, you can help more patients and more families and cover more genes and mutations in one go.”

Optogenetics is an advanced form of gene therapy that introduces a light-sensitive protein into the remaining retinal cells and could hypothetically demonstrate improvement in vision. Lam noted that he has tried other novel approaches, including pulling in vivo stem cells into the affected retina.

“I think there’s a very broad field, it’s exciting,” Lam said. “If I were talking, let’s say 10 years ago, I’d probably be talking about 5 studies. But now we’re talking about 20, 30 studies in the field, so I think there is definitely a blossoming of the different strategies and there are more studies.”

A Shot in the Dark

The next decade may lead to another approval for retinitis pigmentosa, as the previous 10 years helped elucidate how subtypes of RP progress differently. Now, the challenge to overcome is how to slow down the progression and potentially improve vision in those with retinitis pigmentosa.

“When I began specializing in this disease, when I did my PhD, as a clinician in genetic eye diseases, people questioned the wisdom of choosing this specialty,” Singh said. “Because, at that time, there was not much going on in terms of new treatments. It was widely considered an incurable disease.”

The pivotal role of organizations like the Foundation Finding Blindness may prove a major force in promoting research of inherited retinal diseases and providing greater funding to do so. Now, the future may, in fact, be brighter for those with retinitis pigmentosa.

“I think all of this will conspire to hopefully give us at least one, if not several new treatments for this condition over the next few years,” Singh said. “I believe, in my professional lifetime, we will be looking at actually having different options for patients with retinitis pigmentosa and being able to choose the best treatments to tailor to the individual patient.”


  1. Retinitis pigmentosa - statpearls - NCBI bookshelf. (2023, February 19). Retrieved March 30, 2023, from
  2. Boyd, K. (2022, September 9). What is retinitis pigmentosa? American Academy of Ophthalmology. Retrieved March 30, 2023, from
  3. What is retinitis pigmentosa? Foundation Fighting Blindness. (n.d.). Retrieved March 30, 2023, from