Recalibrating Your Approach to Retinitis Pigmentosa

This article is from June 2006 and may contain outdated material.

Retinitis pigmentosa (RP) affects 50,000 to 100,000 people in the United States and several million people worldwide. It is incurable and remains an important cause of blindness.

But considerable progress has been made in understanding the genetics of RP, and investigational therapies are being tested in both animal models of retinal degeneration and in affected humans, giving retina specialists and their patients reasons for hope. “We’re curing animals with various forms of RP, and that would imply that it should be possible to move into effective treatments for people,” said John R. Heckenlively, MD, professor of ophthalmology and visual sciences at the University of Michigan, Ann Arbor.

Strides in Genetics

Genetic research is transforming the way ophthalmologists think about RP. Gene therapy, involving the replacement of defective genes with functional ones, is at or near the top of the list of cutting-edge therapies. The most promising approach would involve using vectors such as recombinant adeno-associated virus to deliver new genes to the retina.

“Gene therapy isn’t being done in humans yet because of uncertainty about the safety of vectors and concerns about the risk of complications when injecting viruses into the eye,” said Dr. Heckenlively. Nevertheless, human trials for gene therapy for RP and other eye diseases are moving closer to reality.

“With gene therapy, one possible approach is to intervene to protect the retina before very much injury has occurred,” said Edwin M. Stone, MD, PhD, professor of ophthalmology and visual sciences at the University of Iowa, and a Howard Hughes Medical Institute investigator.

Ferreting through the genome. Molecular genetic technology has identified many genetic mutations causally linked to RP. By some accounts, there are more than 90 different mutations that result in subtypes of RP, and as testing mechanisms become more sophisticated and more available, many researchers believe it will be important to identify the precise genetic mutation in each patient with RP. (A list of discovered genes is available at www.sph.uth.tmc.edu/RetNet.) “In the past, we had to follow an RP patient for five to 10 years to get an idea of the severity of the disease,” said Dr. Heckenlively. “But if we know the mutation in a patient’s gene, we may be able to give him a more accurate prognosis, provide him with genetic counseling, and put him in line to participate in clinical trials involving that particular gene.”

Test without rest. At major retinal care centers, testing can identify the more common RP mutations relatively quickly. “But it may take much longer for rarer mutations because they tend to be checked for down the line,” said Dr. Heckenlively. “Fifty percent of the time, we’re successful in getting an answer within about two years if the RP patient has a Mendelian pattern of inheritance.”

Testing is currently available for mutations in three genes for dominant RP. A new test for X-linked RP is expected to become available this year. The real challenge, however, is to develop testing for recessive RP because of its genetic heterogeneity and the involvement of more than 50 genes. “Our own test for recessive RP is still in development,” said Dr. Stone of his lab’s work at the University of Iowa, “but we’re hoping to offer patients testing for recessive RP later this year.”

Last September, researchers at the University of Michigan’s Kellogg Eye Center described a newly developed arRP-I sequencing array (referring to the autosomal-recessive RP genotypes), a microchip that can rapidly and simultaneously analyze up to 100 different genes and screen them for mutations. In an analysis of DNA samples from 35 patients with autosomal-recessive RP, the new arRP-I chip determined nearly 98 percent of the tiled sequence with more than a 99 percent accuracy and reproducibility.¹

Bring it to the community. Routine genetic testing has not been available to physicians and patients who live hundreds or even thousands of miles from major labs. “For years,” said Dr. Stone, “when I’d talk about molecular diagnosis, community doctors would respond by saying, ‘You can test your patients because of your research, but this testing isn’t available to the rest of us.’” But the Carver Family Center for Macular Degeneration at the University of Iowa has recently launched a large-scale nonprofit program, offering genetic testing for RP and other inherited eye diseases to any physician and patient, no matter where they are located. Similar programs are operational at several academic centers around the country (see “Get Your RP Test Here”). 

Beyond the Tests: The Treatments

Nutritional therapies. For years, vitamin A therapy has been recommended for many RP patients, based on research dating back to the early 1990s. A randomized, controlled trial of vitamins A and E found that 15,000 IU a day of vitamin A palmitate could slow the course of the condition among adults with typical forms of RP. Vitamin E at a 400 IU a day dose appeared to have an adverse effect on the course of RP in the same study.²

Eliot L. Berson, MD, professor of ophthalmology at Harvard University, said that in concurrence with the recommendation of a data and safety monitoring committee selected by the NEI, he and his coworkers advise that most adults with RP should take vitamin A palmitate, 15,000 IU a day, if their fasting serum vitamin A and liver function are normal. Beta carotene, a retinol precursor, is unreliably converted into vitamin A, he said, and therefore is not a suitable substitute.

No toxic side effects have been associated with this level of vitamin A in patients followed for many years, said Dr. Berson. However, vitamin A supplements are not recommended for women who are pregnant or planning to become pregnant because of the increased risk of birth defects.

Another study among adult patients with RP has shown that an omega-3 rich diet containing docosahexaenoic acid can further slow disease progression.³ Such a diet would call for one to two 3-ounce servings per week of oily fish such as salmon, tuna, herring, mackerel or sardines. Researchers estimated that the combination of vitamin A plus this diet could provide almost 20 additional years of useful vision for adults who start the regimen in their 30s.

Some rare forms of RP have also yielded to nutritional treatment, including hereditary abetalipoproteinemia (Bassen-Kornzweig syndrome) and hereditary phytanic acid oxidase deficiency (Refsum’s disease).

Growth factors. Animal models of retinal degeneration suggest that treatment with specific growth factors may be a way to slow RP progression in people with mild or later-onset disease. Human trials are on the drawing boards, but because particular growth factors might not be effective in all forms of RP, “it may make sense to start treatment trials in subtypes of RP that have responded in animal studies,” said Dr. Stone. “This is another case in which knowing the specific molecular basis of a patient’s disease will be necessary for enrollment in such a trial.”

In a phase 1 study at the NEI, an intravitreal implant of functioning human retinal cells was used to provide RP-affected eyes with ciliary neurotrophic factor (CNTF) in a sustained manner, with the goal of interfering with the degeneration of photoreceptor cells. In March, investigators led by NEI director Paul A. Sieving, MD, PhD, reported that the use of the implant to deliver CNTF into retinal tissue was safe and well tolerated. Three of seven advanced RP patients showed improvements in visual acuity.⁴

Stem cells. For RP patients who have already experienced significant vision loss, degenerated photoreceptors might be replaced someday through stem cell transplantation.

A study led by Martin Friedlander, MD, PhD, professor of cell biology at the Scripps Research Institute in La Jolla, Calif., showed that stem cells may preserve visual function in mice. The investigators selected adult, lineage-negative hematopoietic stem cell populations derived from the bone marrow of both mice and humans, and injected them intravitreally into mice. At the site of the retinal vasculature, these stem cells produced profound vasculotrophic and neurotrophic effects. This rescue effect continued up to six months following injection.⁵

Retinal implants. Advances in microtechnology have facilitated studies of artificial devices designed to restore visual function in RP, with research and actual implantation procedures performed at several sites, including the Doheny Eye Institute in Los Angeles, the Wilmer Eye Institute in Baltimore and the Massachusetts Eye and Ear Infirmary in Boston.

Some of these implants are designed to stimulate the retina from an epiretinal location; electrodes are implanted on the retinal surface, and these electrodes are wirelessly stimulated by signals transmitted from a camera positioned outside the body. Another approach uses subretinal prostheses to activate the residual retina in patients with early- to advanced-stage RP. With one such device, called the Artificial Silicon Retina (ASR) microchip, incident light strikes the chip’s 5,000 microphotodiodes and is converted to an electric current that may be exciting adjacent retinal cells through a neurotrophic mechanism.

Alan Y. Chow, MD, assistant professor of ophthalmology at Rush University Medical Center in Chicago and founder of Optobionics (developers of the ASR chip), plans to present new data later this year on the visual status of 30 RP patients implanted with the device between 2000 and 2005. “On both objective and subjective bases,” he said, “a number of patients, though not all, experienced significant and sometimes life-impacting improvements in vision, including improvements in resolution, contrast, colors and expanded visual field.” But, according to Dr. Chow, “RP is a heterogeneous combination of conditions, and in upcoming evaluations we’d like to determine why there is greater apparent improvement in some patients than in others.”

The jury is still out on the ultimate success of retinal protheses. “A major obstacle they’re encountering is that they’re trying to interface an electrical stimulation device with a biologic system,” said Dr. Heckenlively. “And they’ve had limited success thus far in restoring any meaningful sight.” 

Clinician and Patient, Face to Face

Finally, patients should be offered hope as well as honesty. “Don’t tell patients that there’s nothing they can do,” said Dr. Stone. “Patients need to know that there are researchers working hard on this disease, that significant progress is being made, and that there is reason for optimism.”

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1 Mandal, M. N., et al. Invest Ophthalmol Vis Sci 2005;46:3355–3362.

2 Berson, E. L., et al. Arch Ophthalmol 1993;111:761–772.

3 Berson, E. L., et al. Arch Ophthalmol 2004;122:1306–1314.

4 Sieving, P. A., et al. Proc Natl Acad Sci USA 2006;103:3896–3901.

5 Otani, A., et al. J Clin Invest 2004;114:764–774.