NORD gratefully acknowledges Alessandro Iannaccone, MD, MS, FARVO, Professor of Ophthalmology, Director, Duke Center for Retinal Degenerations & Ophthalmic Genetic Diseases and Duke Eye Center Visual Function Diagnostic Laboratory, Duke University Medical Center; and Jay Berdia, MD, Medical Retina Fellow, Duke Eye Center, and for assistance in the preparation of this report.
Retinitis pigmentosa (RP) comprises a large group of inherited vision disorders that cause progressive degeneration of the retina, the light sensitive membrane that coats the inside of the eyes. Peripheral (or side) vision gradually decreases and eventually is lost in most cases. Central vision is usually preserved until late in these conditions. Some forms of RP can be associated with deafness, obesity, kidney disease, and various other general health problems, including central nervous system and metabolic disorders, and occasionally chromosomal abnormalities.
RP usually begins as night or dim light visual impairment (that is, difficulty in seeing in dimly lit environments or at dusk, or adapting to, or recovering function in, dim light after being in bright light for any length of time). Typically, this is followed by the affected individual’s growing awareness of a loss of peripheral vision. Symptoms are more often noticed between the age 10 and 40, but earlier and later onset forms of RP exist. Characteristically, symptoms develop gradually over time. The sudden onset of these same symptoms should point to a different cause, such as an autoimmune process. Older people with sudden onset of these symptoms are especially at risk for experiencing them as the result of having cancer (so called paraneoplastic retinopathy, which often co-occurs with an optic nerve involvement as well).
The rate and extent of progression of visual loss in RP can vary. The way that peripheral vision is lost in RP has been especially well characterized by various authors. It has been reported in various studies that the most variable aspect is the age of onset of the symptoms. This can vary not only between families and between subtypes of RP, but also within families. However, after that, the rate and modality of progression tends to follow a fairly predictable and stereotyped exponential pattern. This pattern signifies that, during the first decade of symptomatic disease patients experience a slower rate of disease progression, which then accelerates during the subsequent two decades, to slow again during the remainder of life. When other members of a family are affected, the rates of progression are often similar within that family, but some degree of variability exists in this aspect of RP too.
Some patients with RP or related disorders present with complex manifestations affecting other organs, termed “syndromes”. The most common associations of RP with general health (so called “systemic”) problems causing these more complex syndromes are hearing loss and obesity, and are reviewed under the “Related Syndromes” section of this review.
Retinitis pigmentosa is a group of hereditary progressive disorders that may be inherited as autosomal recessive, autosomal dominant or X-linked recessive traits. Maternally inherited variants of RP transmitted via the mitochondrial DNA can also exist.
About half of all RP cases are isolated (that is, they have no family history of the condition). RP may appear alone or in conjunction with one of several other rare disorders. Over 60 systemic disorders show some type of retinal involvement similar to RP.
Autosomal dominant disorders occur when only a single copy of a gene carries a variant (mutation) that, alone, is sufficient and necessary for the appearance of the disease. In dominant disorders, the abnormal gene can be inherited from either parent, or can be the result of a new mutation (termed a “de novo” mutation) in the affected individual. The risk of passing the abnormal gene from an affected parent to offspring is 50% for each pregnancy, regardless of the sex of the parent or of the child. However, in some forms of dominant diseases including some types of dominant RP, patients that inherit the mutated gene will not develop the disease, or will develop a very mild form of it, due to a phenomenon called incomplete penetrance. The RP11 gene (PRPF31) causing autosomal dominant RP is especially prone to doing this, which poses a significant diagnostic challenge. Children who did not inherit the gene variant that causes the autosomal dominant disorder in question, even if born of affected patients, cannot develop the disease.
Autosomal recessive disorders occur when an individual inherits mutations in the same gene from each parent. If an individual receives one normal gene and one gene for the disease, he or she will be a carrier of the disease, but usually will not show symptoms. The risk of two carrier parents both passing the altered gene and having an affected child is 25% with each pregnancy. The risk of having a child who is a carrier, like the parents, is 50% with each pregnancy. The chance of having a child who receives normal genes for that particular trait from both parents is also 25%. The risk is the same for males and females. All children born of a person affected with an autosomal recessive condition will receive one copy of the altered gene from the affected parent. Therefore, they will be healthy carriers like the parents of the affected patient were. A child born of a patient affected with an autosomal recessive condition can be affected only if the affected parent mates with someone who is also a carrier of mutations in the same gene causing disease in the patient. If this happens, then the risk of having an affected child becomes 50%. If an affected person mates with another affected person with a disorder caused by mutations in the same gene, then their risk of having a child affected with that same genetic condition will be 100%, as long as the gene causing the disease in the two parents is the same.
Since most individuals carry a few abnormalities in their genes, parents who are close blood relatives (consanguineous) have a higher chance than do unrelated parents of both carrying the same abnormality in any given gene, which increases the risk of having children with an autosomal recessive genetic disorder. These children will typically carry the same exact change in both copies of their genes (homozygous). However, in most instances, autosomal recessive conditions arise by the serendipitous mating between two unaware healthy carriers, each typically carrying a distinct mutation in the same gene (compound heterozygous).
X-linked recessive genetic disorders are conditions caused by an abnormality in a gene on the X chromosome. Females have two X chromosomes; however, one of the X chromosomes is “turned off” or inactivated during development, a process termed “lyonization”, and all of the genes on that chromosome are inactivated. Lyonization is a random process, and varies from tissue to tissue; within tissues it can also vary from cell to cell. Females who have a disease gene present on one X chromosome are carriers of that disorder. As the result of the lyonization process, most carrier females have about 50% of the normal X and 50% of the mutant X expressed in each tissue, and usually display only milder symptoms of the disorder.
Because of the randomness of the lyonization process, exceptions to this rule exist, particularly if the inactivation of one copy of the X chromosome is significantly “skewed” in favor of one of the copies. If the normal copy prevails, then female carriers can be and remain completely asymptomatic. If the mutant copy prevails, then carrier females can be affected as severely as males. At times, the pattern and ratio of inactivation of the X chromosome will vary between eyes, whereby carriers can present with significantly asymmetric disease (for example, one eye affected severely, and the other much less so). This is not at all uncommon in XLRP carriers.
Unlike females, males have only one X chromosome. If a male inherits an X chromosome that contains a disease gene, he will develop the disease. A male with an X-linked disorder passes the disease gene to all of his daughters, and the daughters will be carriers. A male cannot pass an X-linked gene to his sons because the Y chromosome (not the X chromosome) is always passed to male offspring. A female carrier of an X-linked disorder has a 50% chance with each pregnancy of having a carrier daughter, a 50% chance of having a non-carrier daughter, a 50% chance of having a son affected with the disease, and a 50% chance of having an unaffected son.
In recent years, molecular genetics advances have impacted the understanding and the classification of hereditary retinal diseases perhaps more than any other group of eye diseases, with more than 210 distinct genes mapped (that is, their approximate location on one of the chromosomes has been identified) and over 170 cloned (that is, precisely identified, located, and mutation(s) that cause forms of RP found in them).
RP as a group of vision disorders affects about 1 in 3,000 to 1 in 4,000 people in the world. This means that, with a population of about 324 million in the United States in mid-July 2017 (see < http://www.census.gov/> for continuous updates), about 81,000 to 108,000 people in the United States have RP or a related disorder. With a worldwide population presently estimated at over 7.05 billion, it can be estimated that approximately 1.77 to 2.35 million people around the world have one of these disorders. Excluding age-related macular degeneration and glaucoma, the genetic causes of which are complex and linked simultaneously to more than one gene (so called “polygenic” disorders), RP is the most common cause of inherited visual loss.
RP is diagnosed by electroretinography (ERG) showing progressive loss in photoreceptor function, visual field testing, and retinal imaging [mainly by optical coherence tomography (OCT) and fundus auto-fluorescence (FAF) that show detailed microanatomical features that cannot be resolved by naked eye]. Molecular genetic testing for mutations in many of the genes associated with RP is available to confirm the diagnosis.
The treatment regimen for patients with RP has evolved during the last two decades. A six-year study of patients aged 18 through 49 years conducted at Harvard Medical School with the support of the National Eye Institute and the Foundation Fighting Blindness, showed that those who supplemented their regular diets with 15,000 IU (international units) daily of vitamin A palmitate had a slower decline of retinal function than those who received only trace amounts. It must be noted that vitamin A palmitate is the specific form of vitamin A that was used in this trial. Beta-carotene needs to be metabolized by the liver and broken down into vitamin A before it can be utilized by the body. The rate of absorption and metabolism of beta-carotene varies greatly between individuals and also within the same individual depending on other factors. Beta-carotene, therefore, although a precursor of vitamin A, is not a suitable substitute for vitamin A palmitate. The study results also suggested that taking 400 IU daily of vitamin E supplementation actually hastened the progression of retinal disease, whereby RP patients are recommended against taking vitamin E supplements in addition to what is provided by a regular, balanced diet. This means that virtually all RP patients should not be on generic multivitamins, which are rich in both beta-carotene (but not vitamin A palmitate) and vitamin E, as well as a number of other supplements the effects of which on RP progression are not presently known.
Long-term supplementation with these regimens of vitamin A palmitate appears to be safe, although older patients should be aware that there is some evidence (although not univocal) that vitamin A supplements may promote further bone density loss, worsen osteoporosis and, therefore, increase the risk of hip fractures. In these cases, it may be wise to obtain a baseline bone density scan and, in the presence of existing osteoporosis, treat appropriately the underlying disorder before starting vitamin A supplements and monitor closely the bone density profiles thereafter. In addition, adverse interaction between smoking and beta-carotene has been documented. A 2010 meta-analysis by Druesne et al. that included 9 randomized control trials on β-carotone supplementation confirmed the increased risk of cancer among smokers and asbestos workers taking more than 20 mg/day of β-carotene. Thus, since smokers using such supplements have an increased risk of lung cancer, smokers should not be on vitamin A- or beta-carotene-containing supplements, and smokers with RP should not start vitamin A palmitate supplements until successful completion of a smoking cessation program. Monitoring liver function every 1-2 years while on vitamin A palmitate supplements is advisable even in the absence of liver disease. RP patients with liver disease may not be able to tolerate the full dose of recommended vitamin A supplement, and decision on use and dosage should be made individually by treating physicians.
It should also be noted that more is not better. Because long-term high-dose vitamin A supplementation (e.g., exceeding 20,000 IU) may cause certain adverse effects such as liver disease, patients should not undertake such high supplementation regimens unless so recommended by their treating physician and unless regularly monitored for liver function status when taking such supplementation.
Supplementation has not been formally studied in children. Therefore, the dosage to be given to children with RP is not exactly known. However, one can assume the dosage of 15,000 IUs to be intended for an adult of average body weight of 80 Kg (approx. 175 lb). From these values, the 15,000 IUs daily dose could then be extrapolated to 188 IUs per Kg of body weight (or about 86 IUs per lb. of body weight) and adjusted empirically accordingly used the 2000 growth charts freely available at the CDC website. Furthermore, vitamin A use can cause malformations of the fetus during pregnancy. The highest risks have been identified in women taking more than 10,000 IUs of vitamin A daily (identified as a threshold level) and especially those taking high supplements during the first 7 weeks of gestation. Above this dosage, the risk for certain specific malformations was estimated at about 1 in 57 (hence, about 1.8%). Therefore, women of childbearing age should be careful while on vitamin A supplements and either avoid becoming pregnant while on the 15,000 IU daily supplements, or monitor the frequency of their menstrual cycles while on supplementation and interrupt or reduce promptly vitamin A supplements as soon as they become aware of being pregnant. Women intending to become pregnant should consider reducing supplementation to less than 10,000 IUs daily, or perhaps discontinuing altogether the vitamin A supplements during period of active attempts to conceive. However, it does not appear that vitamin A use during pregnancy should be completely avoided. The use, and dose, of any supplements during or around pregnancy should be carefully discussed by individual patients with their doctors.
Further studies by the same group at Harvard have shown that additional, short-term benefits can be obtained by treating naive RP patients with 15,000 IU of daily vitamin A palmitate in combination with 1,200 mg of docosahexaenoic acid (DHA), an omega-3 fatty acid that is a key component of fish oil. In addition, current treatment recommendations include an omega-3 rich fish diet for those already on vitamin A supplements, since subgroup analyses suggest potentially harmful effects of initiating DHA supplementation while already on the vitamin A supplements.
Additional studies from the same group at Harvard have more recently reported a reduction in the rate of visual field sensitivity loss in RP patients that took 12mg of daily lutein added to the previously studied 15,000 IU vitamin A supplementation regimen compared to those on vitamin A alone.
Another recently completed trial was a specific one of DHA supplementation in children and young adults with X-linked RP, which was conducted at the Retina Foundation of the Southwest (ClinicalTrials.gov identifier: NCT00100230). This trial tested the potential benefits of a higher dose of DHA than that previously tested on the same type of RP. The results do not show a statistically significant reduction in loss of electroretinographic function as compared with placebo however there was a significant reduction in visual field loss in the DHA group.
A review by Brito-Garcia et al. that includes 7 studies on the effectiveness of nutritional supplementation in retinitis pigmentosa found that vitamin A, lutein, and β-carotene showed a small protective effect on the progression of RP. Supplementation with DHA was not shown to have strong evidence of efficacy in RP. None of the studies reported any severe adverse effects of supplementation.
Patients with less common disorders that may be associated with RP were not evaluated in these supplementation studies. In addition, certain patients were not included, such as patients with severely advanced RP. Thus, based on the results of these studies, precise recommendations cannot be made regarding vitamin A supplementation for these patients.
Treatment of Cystoid Macular Edema
A common complication of RP is the formation of small pockets of fluid in the centermost part of the retina, called cystoid macular edema, or CME. CME can cause significant reduction in central visual acuity, as well as blurred vision, and glare. If untreated, further degenerative changes in the retinal tissue will ultimately occur, and the development of a macular hole by rupture of a central larger cyst can also occur. With the current imaging techniques available in the clinical setting to ophthalmologists and other eye care providers, detection of CME changes has become much easier and much more precise. A study with such techniques estimated the frequency of cystic macular changes consistent with CME to be 38% in at least one eye and 27% in both eyes of RP patients. This complication can be successfully treated with oral (tablets) or topical (eye drops) medications of the family of the so-called carbonic anhydrase inhibitors (CAIs), such as acetazolamide or metazolamide (tablets) and dorzalamide or brinzolamide (topical eye drops). While not all patients will respond to these treatments, these medications have been shown to diminish and often eliminate the cystic changes in the retina of RP patients, improving visual acuity in the short term and improving the overall functional prognosis over the long term. Some side effects can result from use of these medications, but most of them can be managed. Patients allergic to sulfonamides should not be taking CAIs. CAIs have been shown to be effective in reducing or resolving cystic changes also in patients with similar findings due a different problem, called macular retinoschisis, as it is seen in patients with ESCS or another hereditary vitreo-retinal disorder, called X-linked retinoschisis.
Since an inflammatory component to CME is also likely, and an increased frequency of certain antibodies in the bloodstream of RP patients with CME has been reported, corticosteroids utilized off-label and injected around (that is, periocularly) or directly inside the eye ball (that is, intravitreally) of RP patients with CME have also been tried in some patients that do not respond to CAIs, and variable success has been reported. However, the intravitreal use of these medications increase the risk of other complications, such as glaucoma or cataract, and a small but serious risk of infection inside the eye ball (endophthalmitis) exists with all intravitreal injections. Periocular injections pose a much lower risk of glaucoma and cataracts, and do not pose a risk of endophthalmitis. A newer formulation of triamcinolone acetonide specifically designed for intravitreal injection has become available in more recent years. Implantable slow-release steroid-laden (dexamethasone and fluocinolone acetonide) devices have also become available. For example, intravitreal dexamethasone implant has been shown to improve anatomic and functional outcomes in refractory CME associated with RP. Initial reports show repeated injections of the implant may be needed to prevent recurrence.
A National Eye Institute sponsored pilot study of 5 participants (ClinicalTrials.gov identifier: NCT02140164) suggested that 100mg twice a day of minocycline, a tetracycline antibiotic, reduced CME associated with RP. This too appears due to anti-inflammatory properties of minocycline.
For individuals with RP, low-vision aids and other assistive devices may be of benefit as vision worsens (see below). In addition, genetic counseling will be of benefit for affected individuals and their families. Although a study of light deprivation in RP was conducted many years ago without benefit, the concern that light damage may play a role in worsening retinal degeneration in some forms of RP remains. This concern is in part supported by recent evidence that, in a dog naturally affected with RP resulting from a mutation in the rhodopsin (RHO) gene, evidence for light-induced worsening of the disease has been obtained. Therefore, to err on the side of caution, use of sunglasses in the outdoors and avoiding undue and unnecessary exposure to excessive amounts of light is generally recommended to all RP patients.
Assistive devices. The Canadian company eSight has created a portable headset visual aid which uses a high resolution camera along with patented processing algorithms to send high speed video to two screens positioned in front of the user’s eyes. The screens can be adjusted and placed in a position that provides the best view for the individual. The high speed camera and processing algorithms provide a clear picture with minimal latency to reduce nausea and balance disturbance that can be experienced with immersive technologies. This technology may allow individuals to become more independent by increasing ability to perform activities of daily living. The newest eSight3 device is currently available for purchase. The company does provide assistance with the cost by various public and private funding sources.
A similar technology that is also available for purchase is the MyEye device, made available by Orcam. small assistive device that fits unobtrusively on any eye glass frame. This technology allows the user to point at objects, surfaces, or labels and read written text on them, recognize familiar faces, identify products by simply pointing at them or looking in that direction. For example, up to 100 faces and 150 commonly used products can be stored in the device for automated recognition.
There is no such thing as a one-size-fits-all device. Each patient may have different needs, issues, and abilities. Thus, it is highly recommended that patients interested in trying any of these assistive devices reach out to local low vision and occupational therapy (LV/OT) specialists to try them out first and obtain direct, unbiased counseling about them from these providers. In the absence of such options locally and should patients be unable to arrange for travel to go see a LV/OT specialist, patients can contact the manufacturers directly via their websites and make arrangements to try the devices directly with them.
After many years of successful studies in animals affected by RP, an exciting new development in the field of RP research is the outcome of three independent human clinical trials of gene therapy for LCA caused by RPE65 gene mutations. Participants in these trials have been treated with one or more injections under the retina of specially engineered viral particles containing normal copies of the RPE65 gene for delivery to the diseased cells of affected patients. All three of these milestone studies, using different means of assessment of visual function, have demonstrated improved vision in virtually all patients. These very encouraging studies open the possibility that correction of the underlying genetic defect inside the retina via gene therapy may be used to treat most, if not all, forms of RP and related disorders. However, additional studies are required to verify this possibility and to identify the appropriate “therapeutic window” within which efficacy of gene therapy can be achieved and maximized. In addition, there is evidence that, despite improvements experienced by patients after receiving gene therapy treatments, the disease progression in the treated areas may still occur over time. Thus, further refinement of gene therapy approaches, including increasing the levels of gene expression in the target cells, remain underway.
Very recent, encouraging studies of gene therapy in a naturally occurring canine model of X-linked RP linked to mutations in the RPGR gene have laid the groundwork for human gene therapy trials also of this form of RP and this UK study is currently recruiting participants (ClinicalTrials.gov identifier: NCT03116113). Other human, Phase I/II gene therapy trials are presently ongoing around the world for choroideremia. In the US there are multiple sites (ClinicalTrials.gov identifiers: NCT02341807 and NCT02553135), in Germany (ClinicalTrials.gov identifier: NCT02553135), and in the UK (ClinicalTrials.gov identifier: NCT01461213). Additional gene therapy trials are presently ongoing or ABCA4-linked recessive Stargardt macular dystrophy (ClinicalTrials.gov identifier: NCT01367444), X-linked retinoschisis (ClinicalTrials.gov identifier: NCT02317887) and for Usher syndrome type IB linked to mutations in the MYO7A gene (ClinicalTrials.gov identifier: NCT01505062). More such trials for other conditions are expected in the next few years.
Gene therapy is possible only in patients whose disease genetic cause has been discovered; additionally, gene therapy for types of RP other than a recessive one like LCA has yet to be tried in humans. Presently, this treatment is not possible for all RP patients, and for some it may become possible only in quite a few years from now. Therefore, other treatment strategies remain important to use and pursue.
Treatment strategies that can be used as an alternative to, or in addition, to, gene therapy can be gene-specific or gene-independent ones.
As with gene therapy, to benefit from these treatments, patients need to know the specific genetic cause of their individual disease. Molecular genetic diagnostic testing is now available for most if not all genes. Therefore, when possible, testing under the guidance of an experienced ophthalmic geneticist is strongly recommended for all patients, as this can not only provide far greater diagnostic accuracy, but also open the door to a variety of emerging and forthcoming treatment options.
Other than gene therapy itself, treatments falling in this category are directed at genetically defined groups of patients that are more likely to respond to a certain treatment depending on certain genetic characteristics. Examples of this include:
a) Patients that share a certain type of mutation: for example, nonsense mutations that lead to truncation of the protein produced by the gene in question can be in theory overcome by certain drugs. This type of drug is currently being studied in a pulmonary disease known as cystic fibrosis. Retinal disorders in which nonsense mutations are particularly common include choroideremia and, to a lesser extent, certain forms of X-linked RP, but nonsense mutations have been reported for nearly every form of RP and related disorders. Therefore, if such treatments were to be proven safe and effective, there is a possibility that patients with any form of RP may benefit from such drugs if their disease is caused by this category of mutations.
b) Patients with mutations in different genes but that result in the same net molecular effect: for example, mutations that result in overall misfolding of the encoded protein could be partially overcome by molecules that exert a chaperone effect. One such drug of this type may be valproic acid (VPA), a drug long known as an effective medication for seizure disorders. A study on misfolded molecules of rhodopsin, which is a common cause of dominant RP, showed that VPA is capable of improving the folding of mutated molecules responsible for dominant RP. This suggests that patients with genetic mutations affecting the folding of the encoded protein may benefit from VPA and, since misfolding is a common problem in dominant RP and anecdotal, open-label evidence suggests that VPA may be able to improve visual field size in dominant RP, a Phase II trial of VPA on patients with dominant RP (ClinicalTrials.gov identifier: NCT01233609) has been completed and study results are pending. The exact VPA dose that may be effective in RP, if any, is not presently known, and VPA can have serious side effects, especially in pregnant women. Therefore, RP patients are strongly cautioned to await the outcome of this double-masked, randomized, placebo-controlled multi-center trial before requesting VPA prescriptions of any dosing from physicians.
c) Patients sharing mutations in the same gene leading to same, disease-causing downstream defect: for example, diseases in which a certain carotenoid molecules indispensable for vision cannot be recycled because of a defect in the enzyme needed to complete the recycling process could be overcome by treating patients with a synthetic version of the needed carotenoid that bypasses the enzymatic defect. One such example is (an ongoing trial of) a synthetic derivative of vitamin A, called compound QLT091001. The enzyme produced by the LRAT gene is necessary for the recycling of specially shaped molecules of vitamin A that rods in the retina need for night vision. When this recycling process is disrupted due to mutations in the LRAT gene, patients experience night vision problems and develop a form of recessive RP. Oral administration of QLT091001 on an experimental, open-label basis in patients with RP resulting from LRAT mutations has been reported to significantly improve their visual field. For this reason, two trials of QLT091001 are presently completed (ClinicalTrials.gov identifiers: NCT01014052 and NCT01521793) with results listed as pending.
These approaches are aimed at providing benefit to retinal health across the board, regardless of the genetic cause. The nutritional treatments like vitamin A palmitate and lutein illustrated previously fall in this category. Other such examples include:
Ciliary neurotrophic factor (CNTF). One such treatment that is presently being studied in clinical trials of RP is a growth factor, known as ciliary neurotrophic factor, or CNTF, delivered to the retina via tiny porous capsules in which live cells engineered to produce a specific amount of CNTF are trapped and held in place by special scaffolding. The specially designed porous nature of the capsule allows nutrients to enter while also allowing CNTF to leave the capsule, for slow release inside the vitreous cavity of the eye ball and diffusion to the retina. A Phase I safety trial, which not only showed excellent safety but also suggested possible improvements in some aspects of visual function in some of the treated eyes, has been successfully completed.
CNTF Phase II/III clinical trials with this special proprietary device at a dozen different sites across the United States have been recently completed. Two trials of RP have been recently completed: the CNTF3 trial aimed at assessing the efficacy of the CNTF-releasing implants on visual acuity in advanced RP one year after the implants had been placed in the eye; the CNTF4 trial was a 2-year trial aimed at assessing the efficacy of the implants on visual sensitivity across the central visual field in patients with earlier stages of RP. Additionally, a CNTF2 trial was conducted on patients with the dry form of age-related macular degeneration (dry AMD or “geographic atrophy”). These Phase II/III trials confirmed the safety of the implanted devices, but did not achieve their therapeutic objectives, whereby treatment with CNTF-releasing implants cannot be considered a suitable treatment for RP or dry AMD at this time. However, some encouraging post-trial sub-analyses indicated that the implants did exert some effect. Retinal thickness was consistently higher in treated eyes than the fellow eyes that did not receive the implants across all three trials. Also, studies of macular cones by means of an emerging imaging technique based on the principle of “adaptive optics” suggested that macular cones may have been better preserved in eyes that received the implants than the fellow eyes. Neither of these were primary outcome measures for the CNTF trials, whereby these reasons were insufficient to deem the implants effective by FDA standards. Long-term follow up of treated patients is still in progress to determine if a favorable effect of the implants may be detected at later time points. Whether CNTF will be reconsidered for investigation in RP, AMD and related diseases in the future is not presently known. The CNTF trials did show, however, that the device is safe and, therefore, could be used with different treatments in the future, and suggested that inclusion of imaging outcomes in future trials may be able to capture response to treatment better than global functional outcomes. It is still somewhat uncertain how to best relate imaging outcomes to standard and widely accepted visual function outcomes such as visual acuity and visual fields.
Brimonidine tartrate. One more recently completed study is that of a micro-implant, called posterior segment drug delivery system, that is injected inside the vitreal chamber of the eye ball and that is designed to release over time a medication, called brimonidine tartrate (ClinicalTrials.gov identifier: NCT00661479). Three different dosages of this medication were tested in one eye of patients with RP (at a single study site in the United States and at three sites in Europe). This medication has existed on the market as an eye drop to lower eye pressure in patients with glaucoma for numerous years. Several lines of evidence suggested that brimonidine tartrate has neuroprotective potential on the optic nerve. Additional in vitro studies demonstrated the strong neuroprotective potential of this specific drug on degenerating rod and cone cells in the retina. These findings added to other studies on related compounds, which also had shown significant retinal neuroprotective potential. Despite the significant potential displayed by brimonidine tartrate, difficulties in delivering an adequate dose to the retina via the use of simple eye drops, combined with a relatively high frequency of intolerance to topical administration, limited the applicability of this potential treatment. The new delivery strategy that has been developed by the sponsoring company to this trial opens the door to a reappraisal of this treatment strategy and its possible utilization to afford neuroprotection to the degenerating retina of RP patients. Results of this Phase I/II trial were recently published and showed modest changes in vision and contrast sensitivity in the implanted eyes. Implantation was associated with considerable risk, 2 of the 21 participants’ experienced severe adverse effects such as syncope and myelitis.
Antioxidants. Oxidative damage has been shown to be a major contributor to cone cell death in animal models of RP. It has been shown that promotion of cone survival is possible in mice treated with a derivative of N-Acetylcysteine (NAC), an effective antioxidant with an excellent safety profile and utilized for decades in Europe for the treatment of other, unrelated conditions. A phase 1 clinical trial is presently testing the effect of oral NAC in RP (ClinicalTrials.gov identifier: NCT03063021).
Recombinant human nerve growth factor (hNGF). There is an ongoing randomized phase II clinical trial (ClinicalTrials.gov identifier: NCT02609165) that is investigating the therapeutic potential for recombinant human nerve growth factor eye drops in treating RP. Recombinant hNGF has been shown to promote photoreceptor survival in mouse models of RP. In addition, a pilot study testing recombinant murine NGF eye drops in 8 patients with advanced RP found no serious adverse effects or loss of visual function. A minority of these patients showed a trend towards improvement in visual function by visual field and electroretinographic testing.
Tissue Transplantation. A Phase II trial of fetal retinal tissue transplantation into the eyes of patients with advanced RP has been completed (ClinicalTrials.gov identifier: NCT00345917). Interim results after one year of follow up in one of the participating subjects have been reported, suggesting no rejection of the transplanted tissue and progressive and sustained improvement of visual acuity from 20/800 at baseline to 20/160 at one year. Enrollment in this study, which aimed at recruiting 10 subjects, has been completed and results have not been posted.
Human retinal progenitor cells. There is currently an ongoing clinical trial testing the safety of injection of human retinal progenitor cells in retinitis pigmentosa (ClinicalTrials.gov identifier: NCT02320812). Early results have been promising and the study will be progressing to phase II. Results are expected within the next few years. As a note of caution there is evidence of severe visual loss including complete blindness after ocular injection of autologous adipose derived “stem cells” from an unregulated clinic in the United States. There were no clinical trials that supported these treatments and it is of utmost importance to wait for the results of clinical trials that test the safety and efficacy of these new treatments before undergoing treatment.
Transcorneal electrical stimulation (TES). Ocular electrical stimulation has been tried for a variety of ophthalmic conditions ranging from glaucoma to amblyopia while more recent interest has been focused on traumatic or nonarteritic optic neuropathy or longstanding retinal artery occlusion. A recent 1 year prospective randomized and partially blinded study was conducted on 24 RP patients. TES was applied for 30 minutes a week for 6 weeks in the treatment groups. The study found that TES was safe to use in RP. The results pointed towards a positive trend. Statistically significant improvements in visual field loss and ERG response were found among the group treated with the highest amplitude of stimulation. In the absence of conclusive evidence in favor of the efficacy of this treatment approach, however, this method remains experimental and is not yet recommendable as of proven efficacy.
Acupuncture. Anecdotal reports exist that acupuncture may be of benefit to RP. To date, however, there are no peer-reviewed publications to support the alleged benefits of this treatment approach and, while not known to be harmful, these treatments are certainly not inexpensive. Thus, patients with RP and related disorders are cautioned from engaging in treatment sessions of unproven efficacy until conclusive results will be published in the peer-reviewed literature.
These approaches are also essentially gene-independent, but are at this time reserved for end-stage RP patients who are no longer eligible for other treatment approaches, and presently include the following:
Artificial retina implants. Patients with severe vision loss to light perception or less in both eyes are eligible to receive this type of approach. Artificial retina implants are of two different types: subretinal (i.e., implanted under the retina) and epiretinal (i.e., implanted on the surface of the retina). From a therapeutic standpoint, the farthest ahead in the approval process is the Argus II epiretinal implant, A Phase II clinical trial entitled, “Argus” II Retinal Stimulation System Feasibility Protocol to test the safety and efficacy in restoring visual acuity in patients with very advanced RP (with a residue of bare light perception or less in each eye) was recently completed. The Argus II artificial retina implant was developed by Second Sight in conjunction with the Artificial Retina Project Consortium sponsored by the Department of Energy. This trial was conducted at several sites in the US, Enrollment in this trial is presently completed (ClinicalTrials.gov identifier: NCT00407602). Preliminary results have been reported and appear very encouraging. A recent study showed that twenty-four of 30 patients remained implanted with functioning Argus II Systems at 5 years after implantation. Patients performed significantly better with the Argus II on than off on all visual function tests and functional vision tasks. A review of Argus II implantation studies found improvements in quality of life and visual outcomes along with a high cost of implantation among those treated with the Argus II. The Argus II device is presently FDA approved and largely Medicare covered from implantation in patients with RP. Rehabilitative measures after receiving this implant are necessary to learn well how to benefit from the Argus II implant and to ripen the full benefits of this device.
A subretinal device is being developed in Europe by the German company Retina Implant AG. The electrodes of this implant work essentially the same way as the Argus II implant, but the treatment requires a different surgical approach to insert the implant underneath the retina. A potential advantage of this approach is that no external goggle-mounted camera is required and that the recipient of the implant can continue to look at objects with their natural eye movements. Because of this difference, this type of implant is also being evaluated for patients with macular degeneration. Trials for RP are being considered in the US as well and, if shown to be safe and successful, this technology may represent an important alternative to the epiretinal Argus II approach.
Optogenetics. This treatment approach is a form of gene therapy that is not specific to the gene that causes the primary disease but that utilizes the gene therapy technology (i.e., transferring a gene using modified viral particles) into retinal cells. With optogenetics, though, the genes delivered are light-sensing genes derived from algae that can enhance or provide novel light-sensing properties to cells of the retina that normally do not have them by themselves, such as the bipolar cells (BCs, which are the cells that connect the photoreceptors to the next visual stations, the retinal ganglion cells, or RGCs), or to RGCs, which normally have limited light sensing capabilities on their own. If transfected with one of these algae-derived genes (channelrhsodopsin-2 or halorhodopsin), either BCs or RGCs can acquire the ability to sense light at a much higher level. These light sensing receptors may also be built into actual artificial retina implants, and this possibility is under consideration. In the meantime, though, the basic transfection technology, delivered by intravitreal injection, has advanced rapidly in the development pipeline and is already in Phase I/II human clinical trials for advanced RP (ClinicalTrials.gov identifier: NCT02556736). At this time, this approach is considered mainly an alternative to artificial retina implants for patients with advanced RP with the fundamental difference that only the algae genes are artificially implanted into the retina, but no physical device actually needs to be implanted. It is possible that, if this approach proves to be both safe and effective, further developments may extend to less severe stages of RP and perhaps also to other conditions.
Finally, the Foundation Fighting Blindness provides a summary of clinical trials conducted for RP and other diseases on their website (http://www.fightblindness.org).
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
For information about clinical trials sponsored by private sources, contact:
For information about clinical trials conducted in Europe, contact:
Contact for additional information about retinitis pigmentosa:
Alessandro Iannaccone, M.D., M.S.
Professor of Ophthalmology
Director, Duke Center for Retinal Degenerations & Ophthalmic Genetic Diseases
and Duke Eye Center Visual Function Diagnostic Laboratory
Duke University Medical Center, 2351 Erwin Road, DUMC Box 3802
Durham, NC 27710
Clinic & Diagnostic Lab Coordinator: (919) 684-1857
Email: [email protected]
Adamus G, Ren G, Weleber RG. Autoantibodies against retinal proteins in paraneoplastic and autoimmune retinopathy. BMC Ophthalmol. 2004;4:5.
Ahn SJ, Kim KE, Woo SJ, Park KH. The effect of an intravitreal dexamethasone implant for cystoid macular edema in retinitis pigmentosa: a case report and literature review. Ophthalmic Surg Lasers Imaging Retina. 2014;45(2):160-4.
Apushkin MA, Fishman GA, Grover S, Janowicz MJ. Rebound of cystoid macular edema with continued use of acetazolamide in patients with retinitis pigmentosa. Retina. 2007;27:1112-1118.
Apushkin MA, Fishman GA. Use of dorzolamide for patients with X-linked retinoschisis. Retina. 2006;26:741-745.
Baala L, Audollent S, Martinovic J, et al. Pleiotropic effects of CEP290 (NPHP6) mutations extend to Meckel syndrome. Am J Hum Genet. 2007;81:170-179.
Badano JL, Kim JC, Hoskins BE, et al. Heterozygous mutations in BBS1, BBS2 and BBS6 have a potential epistatic effect on Bardet-Biedl patients with two mutations at a second BBS locus. Hum Mol Genet. 2003;12:1651-1659.
Badano JL, Mitsuma N, Beales PL, Katsanis N. The ciliopathies: an emerging class of human genetic disorders. Annu Rev Genomics Hum Genet. 2006;7:125-148.
Bainbridge JW, Smith AJ, Barker SS, et al. Effect of gene therapy on visual function in Leber’s congenital amaurosis. N Engl J Med. 2008;358:2231-2239.
Bakondi B, Lv W, Lu B, Jones MK, Tsai Y, Kim KJ, Levy R, Akhtar AA, Breunig JJ, Svendsen CN, Wang S. In Vivo CRISPR/Cas9 Gene Editing Corrects Retinal Dystrophy in the S334ter-3 Rat Model of Autosomal Dominant Retinitis Pigmentosa. Mol Ther. 2016;24(3):556-63.
Barrett JM, Berlinguer-Palmini R, Degenaar P. Optogenetic approaches to retinal prosthesis. Visual Neuroscience. 2014;31(4-5):345-54.
Berson EL, Rosner B, Sandberg MA, Hayes KC, Nicholson BW, Weigel-DiFranco C, Willett W. A randomized trial of vitamin A and vitamin E supplementation for retinitis pigmentosa. Arch Ophthalmol. 1993;111:761-72.
Sibulesky L, Hayes KC, Pronczuk A, Weigel-DiFranco C, Rosner B, Berson EL. Safety of <7500 RE (<25000 IU) vitamin A daily in adults with retinitis pigmentosa. Am J Clin Nutr. 1999;69:656-63.
Berson EL, Rosner B, Sandberg MA, et al. Clinical trial of docosahexaenoic acid in patients with retinitis pigmentosa receiving vitamin A treatment. Arch Ophthalmol. 2004;122:1297-1305.
Berson EL, Rosner B, Sandberg MA, et al. Clinical trial of lutein in patients with retinitis pigmentosa receiving vitamin A. Arch Ophthalmol. 2010;128:403-11.
Berson EL, Rosner B, Sandberg MA, et al. Further evaluation of docosahexaenoic acid in patients with retinitis pigmentosa receiving vitamin A treatment: subgroup analyses. Arch Ophthalmol. 2004;122:1306-1314.
Brancati F, Barrano G, Silhavy JL, et al. CEP290 mutations are frequently identified in the oculo-renal form of Joubert syndrome-related disorders. Am J Hum Genet. 2007;81:104-113.
Brito-Garcia N, Del Pino-Sedeno T, Trujillo-Martin MM, Coco RM, Rodriguez de la Rua E, Del Cura-Gonzalez I, Serrano-Aguilar P. Effectiveness and safety of nutritional supplements in the treatment of hereditary retinal dystrophies: a systematic review. Eye (Lond). 2017;31(2):273-85.
Burke J, Schwartz M. Preclinical evaluation of brimonidine. Surv Ophthalmol 1996;41:S9-S18.
Busskamp V, Picaud S, Sahel JA, Roska B. Optogenetic therapy for retinitis pigmentosa. Gene Ther. 2012;19(2):169-75.
Busskamp V, Roska B. Optogenetic approaches to restoring visual function in retinitis pigmentosa. Curr Opin Neurobiol. 2011;21(6):942-6.
Campochiaro PA, Strauss RW, Lu L, Hafiz G, Wolfson Y, Shah SM, Sophie R, Mir TA, Scholl HP. Is There Excess Oxidative Stress and Damage in Eyes of Patients with Retinitis Pigmentosa? Antioxid Redox Signal. 2015;23(7):643-8.
Chan JW. Paraneoplastic retinopathies and optic neuropathies. Surv Ophthalmol. 2003;48:12-38.
Cideciyan AV, Aleman TS, Boye SL, et al. Human gene therapy for RPE65 isomerase deficiency activates the retinoid cycle of vision but with slow rod kinetics. Proc Natl Acad Sci U S A. 2008;105:15112-15117.
Cideciyan AV, Jacobson SG, Aleman TS, et al. In vivo dynamics of retinal injury and repair in the rhodopsin mutant dog model of human retinitis pigmentosa. Proc Natl Acad Sci U S A. 2005;102:5233-5238.
Cideciyan AV, Jacobson SG, Beltran WA, Sumaroka A, Swider M, Iwabe S, Roman AJ, Olivares MB, Schwartz SB, Komáromy AM, Hauswirth WW, Aguirre GD. Human retinal gene therapy for Leber congenital amaurosis shows advancing retinal degeneration despite enduring visual improvement. Proceedings of the National Academy of Sciences of the United States of America. 2013;110(6):E517-E25.
Collin GB, Marshall JD, Ikeda A, et al. Mutations in ALMS1 cause obesity, type 2 diabetes and neurosensory degeneration in Alstrom syndrome. Nat Genet. 2002;31:74-78.
da Cruz L, Dorn JD, Humayun MS, Dagnelie G, Handa J, Barale PO, Sahel JA, Stanga PE, Hafezi F, Safran AB, Salzmann J, Santos A, Birch D, Spencer R, Cideciyan AV, de Juan E, Duncan JL, Eliott D, Fawzi A, Olmos de Koo LC, Ho AC, Brown G, Haller J, Regillo C, Del Priore LV, Arditi A, Greenberg RJ. Five-Year Safety and Performance Results from the Argus II Retinal Prosthesis System Clinical Trial. Ophthalmology. 2016;123(10):2248-54.
den Hollander AI, Koenekoop RK, Yzer S, et al. Mutations in the CEP290 (NPHP6) gene are a frequent cause of Leber congenital amaurosis. Am J Hum Genet. 2006;79:556-561.
DiMauro S, Schon EA. Mitochondrial respiratory-chain diseases. N Engl J Med. 2003;348:2656-2668.
Druesne-Pecollo N, Latino-Martel P, Norat T, Barrandon E, Bertrais S, Galan P, Hercberg S. Beta-carotene supplementation and cancer risk: a systematic review and metaanalysis of randomized controlled trials. Int J Cancer. 2010;127(1):172-84.
Falsini B, Iarossi G, Chiaretti A, Ruggiero A, Luigi M, Galli-Resta L, Corbo G, Abed E. NGF eye-drops topical administration in patients with retinitis pigmentosa, a pilot study. Journal of Translational Medicine. 2016;14:8.
Feskanich D, Singh V, Willett WC, Colditz GA. Vitamin A intake and hip fractures among postmenopausal women. JAMA. 2002;287:47-54.
Fishman GA, Apushkin MA. Continued use of dorzolamide for the treatment of cystoid macular oedema in patients with retinitis pigmentosa. Br J Ophthalmol. 2007;91:743-745.
Fishman GA, Bozbeyoglu S, Massof RW, Kimberling W. Natural course of visual field loss in patients with Type 2 Usher syndrome. Retina. 2007;27:601-608.
Genaro Pde S, Martini LA. Vitamin A supplementation and risk of skeletal fracture. Nutr Rev. 2004;62:65-67.
Ghajarnia M, Gorin MB. Acetazolamide in the treatment of X-linked retinoschisis maculopathy. Arch Ophthalmol. 2007;125:571-573.
Grover S, Apushkin MA, Fishman GA. Topical dorzolamide for the treatment of cystoid macular edema in patients with retinitis pigmentosa. Am J Ophthalmol. 2006;141:850-858.
Hajali M, Fishman GA, Anderson RJ. The prevalence of cystoid macular oedema in retinitis pigmentosa patients determined by optical coherence tomography. Br J Ophthalmol. 2008;92:1065-1068.
Hauswirth W, Aleman TS, Kaushal S, et al. Treatment of leber congenital amaurosis due to RPE65 mutations by ocular subretinal injection of adeno-associated virus gene vector: short-term results of a phase I trial. Hum Gene Ther. 2008;19(10):979-90.
Health Quality Ontario. Retinal Prosthesis System for Advanced Retinitis Pigmentosa: A Health Technology Assessment. Ont Health Technol Assess Ser. 2016;16(14):1-63.
Hearn T, Renforth GL, Spalluto C, et al. Mutation of ALMS1, a large gene with a tandem repeat encoding 47 amino acids, causes Alstrom syndrome. Nat Genet. 2002;31:79-83.
Hearn T, Spalluto C, Phillips VJ, et al. Subcellular localization of ALMS1 supports involvement of centrosome and basal body dysfunction in the pathogenesis of obesity, insulin resistance, and type 2 diabetes. Diabetes. 2005;54:1581-1587.
Henriksen BS, Marc RE, Bernstein PS. Optogenetics for Retinal Disorders. Journal of Ophthalmic & Vision Research. 2014;9(3):374-82.
Hoffman DR, Locke KG, Wheaton DH, et al. A randomized, placebo-controlled clinical trial of docosahexaenoic acid supplementation for X-linked retinitis pigmentosa. Am J Ophthalmol. 2004;137:704-718.
Iannaccone A, Breuer DK, Wang XF, et al. Clinical and immunohistochemical evidence for an X linked retinitis pigmentosa syndrome with recurrent infections and hearing loss in association with an RPGR mutation. J Med Genet. 2003;40:e118.
Iannaccone A, Fung KH, Eyestone ME, Stone EM. Treatment of adult-onset acute macular retinoschisis in enhanced S-cone syndrome with oral acetazolamide. Am J Ophthalmol. 2009;147(2):307-312.e2.
Iannaccone A, Kritchevsky SB, Ciccarelli ML, et al. Kinetics of visual field loss in Usher syndrome Type II. Invest Ophthalmol Vis Sci. 2004;45:784-792.
Iannaccone A, Othman MI, Cantrell AD, et al. Retinal phenotype of an X-linked pseudo-Usher syndrome in association with the G173R mutation in the RPGR gene. Adv Exp Med Biol. 2008;613:221-227.
Iannaccone A, Sarkisian SRJ, Kerr NC, Morris WR. The genetics of glaucoma, cataracts and corneal dystrophies. Comp Ophthalmol Update. 2004;5:307-326.
Iannaccone A, Wang X, Jablonski MM, et al. Increasing evidence for syndromic phenotypes associated with RPGR mutations. Am J Ophthalmol. 2004;137:785-786.
Iannaccone A. The genetics of hereditary retinopathies and optic neuropathies. Comp Ophthalmol Update. 2005;5:39-62.
Is it true that too much vitamin A may increase my risk of bone fractures? Mayo Clin Womens Healthsource. 2003;7:8.
Jacobson SG, Cideciyan AV, Sumaroka A, et al. Remodeling of the Human Retina in Choroideremia: Rab Escort Protein 1 (REP-1) Mutations. Invest Ophthalmol Vis Sci. 2006;47:4113-4120.
Kim JE. Intravitreal triamcinolone acetonide for treatment of cystoid macular edema associated with retinitis pigmentosa. Retina. 2006;26:1094-1096.
Kuriyan AE, Albini TA, Townsend JH, Rodriguez M, Pandya HK, Leonard REI, Parrott MB, Rosenfeld PJ, Flynn HWJ, Goldberg JL. Vision Loss after Intravitreal Injection of Autologous “Stem Cells” for AMD. New England Journal of Medicine.
Lee SY, Usui S, Zafar AB, Oveson BC, Jo YJ, Lu L, Masoudi S, Campochiaro PA. N-Acetylcysteine promotes long-term survival of cones in a model of retinitis pigmentosa. J Cell Physiol. 2011;226(7):1843-9.
Lee TK, McTaggart KE, Sieving PA, et al. Clinical diagnoses that overlap with choroideremia. Can J Ophthalmol. 2003;38:364-372; quiz 372.
Leitch CC, Zaghloul NA, Davis EE, et al. Hypomorphic mutations in syndromic encephalocele genes are associated with Bardet-Biedl syndrome. Nat Genet 2008;40:443-448.
Li G, Vega R, Nelms K, et al. A role for Alstrom syndrome protein, alms1, in kidney ciliogenesis and cellular quiescence. PLoS Genet. 2007;3:e8.
Lim LS, Harnack LJ, Lazovich D, Folsom AR. Vitamin A intake and the risk of hip fracture in postmenopausal women: the Iowa Women’s Health Study. Osteoporos Int. 2004;15:552-559.
Lips P. Hypervitaminosis A and fractures. N Engl J Med. 2003;348:347-349.
Loktev AV, Zhang Q, Beck JS, et al. A BBSome subunit links ciliogenesis, microtubule stability, and acetylation. Dev Cell. 2008;15:854-865.
Maguire AM, Simonelli F, Pierce EA, et al. Safety and efficacy of gene transfer for Leber’s congenital amaurosis. N Engl J Med. 2008;358:2240-2248.
Malm E, Ponjavic V, Nishina PM, et al. Full-field electroretinography and marked variability in clinical phenotype of Alstrom syndrome. Arch Ophthalmol. 2008;126:51-57.
Mansour AM, Sheheitli H, Kucukerdonmez C, Sisk RA, Moura R, Moschos MM, Lima LH, Al-Shaar L, Arevalo JF, Maia M, Foster RE, Kayikcioglu O, Kozak I, Kurup S, Zegarra H, Gallego-Pinazo R, Hamam RN, Bejjani RA, Cinar E, Erakgun ET, Kimura A, Teixeira A. Intravitreal dexamethosone implant in retinitis pigmentosa-related cystoid macular edema. Retina. 2017; Feb 2017 [E-pub ahed of print].
Marshall JD, Bronson RT, Collin GB, et al. New Alstrom syndrome phenotypes based on the evaluation of 182 cases. Arch Intern Med 2005;165:675-683.
Milam AH, Rose L, Cideciyan AV, et al. The nuclear receptor NR2E3 plays a role in human retinal photoreceptor differentiation and degeneration. Proc Natl Acad Sci U S A. 2002;99:473-478.
Minnella AM, Falsini B, Bamonte G, et al. Optical coherence tomography and focal electroretinogram evaluation of cystoid macular edema secondary to retinitis pigmentosa treated with intravitreal triamcinolone: case report. Eur J Ophthalmol. 2006;16:883-886.
Mura M, Sereda C, Jablonski MM, MacDonald IM, Iannaccone A. Clinical and functional findings in choroideremia due to complete deletion of the CHM gene. Arch Ophthalmol. 2007;125:1107-1113.
Mykytyn K, Nishimura DY, Searby CC, et al. Evaluation of complex inheritance involving the most common Bardet-Biedl syndrome locus (BBS1). Am J Hum Genet. 2003;72:429-437.
Nachury MV, Loktev AV, Zhang Q, et al. A core complex of BBS proteins cooperates with the GTPase Rab8 to promote ciliary membrane biogenesis. Cell. 2007;129:1201-1213.
Nachury MV. Tandem affinity purification of the BBSome, a critical regulator of Rab8 in ciliogenesis. Methods Enzymol. 2008;439:501-513.
Nakamura PA, Tang S, Shimchuk AA, Ding S, Reh TA. Potential of Small Molecule-Mediated Reprogramming of Rod Photoreceptors to Treat Retinitis Pigmentosa. Invest Ophthalmol Vis Sci. 2016;57(14):6407-15.
Ozdemir H, Karacorlu M, Karacorlu S. Intravitreal triamcinolone acetonide for treatment of cystoid macular oedema in patients with retinitis pigmentosa. Acta Ophthalmol Scand. 2005;83:248-251.
Priya S, Nampoothiri S, Sen P, Sripriya S. Bardet-Biedl syndrome: Genetics, molecular pathophysiology, and disease management. Indian J Ophthalmol. 2016;64(9):620-7.
Radtke ND, Aramant RB, Seiler MJ, Petry HM, Pidwell D. Vision change after sheet transplant of fetal retina with retinal pigment epithelium to a patient with retinitis pigmentosa. Arch Ophthalmol. 2004;122:1159-1165.
Roberts MF, Fishman GA, Roberts DK, et al. Retrospective, longitudinal, and cross sectional study of visual acuity impairment in choroideraemia. Br J Ophthalmol 2002;86:658-662.
Sacchetti M, Mantelli F, Rocco ML, Micera A, Brandolini L, Focareta L, Pisano C, Aloe L, Lambiase A. Recombinant Human Nerve Growth Factor Treatment Promotes Photoreceptor Survival in the Retinas of Rats with Retinitis Pigmentosa. Curr Eye Res. 2017:1-5.
Sandberg MA, Gaudio AR, Berson EL. Disease course of patients with pericentral retinitis pigmentosa. Am J Ophthalmol. 2005;140:100-106.
Saraiva VS, Sallum JM, Farah ME. Treatment of cystoid macular edema related to retinitis pigmentosa with intravitreal triamcinolone acetonide. Ophthalmic Surg Lasers Imaging. 2003;34:398-400.
Sayer JA, Otto EA, O’Toole JF, et al. The centrosomal protein nephrocystin-6 is mutated in Joubert syndrome and activates transcription factor ATF4. Nat Genet. 2006;38:674-681.
Schatz A, Pach J, Gosheva M, Naycheva L, Willmann G, Wilhelm B, Peters T, Bartz-Schmidt KU, Zrenner E, Messias A, Gekeler F. Transcorneal Electrical Stimulation for Patients With Retinitis Pigmentosa: A Prospective, Randomized, Sham-Controlled Follow-up Study Over 1 Year. Invest Ophthalmol Vis Sci. 2017;58(1):257-69.
Scorolli L, Morara M, Meduri A, et al. Treatment of cystoid macular edema in retinitis pigmentosa with intravitreal triamcinolone. Arch Ophthalmol. 2007;125:759-764.
Sharon D, Sandberg MA, Caruso RC, Berson EL, Dryja TP. Shared mutations in NR2E3 in enhanced S-cone syndrome, Goldmann-Favre syndrome, and many cases of clumped pigmentary retinal degeneration. Arch Ophthalmol. 2003;121:1316-1323.
Sieving PA, Caruso RC, Tao W, et al. Ciliary neurotrophic factor (CNTF) for human retinal degeneration: phase I trial of CNTF delivered by encapsulated cell intraocular implants. Proc Natl Acad Sci U S A. 2006;103:3896-3901.
Srour M, Querques G, Leveziel N, Zerbib J, Tilleul J, Boulanger-Scemama E, Souied EH. Intravitreal dexamethasone implant (Ozurdex) for macular edema secondary to retinitis pigmentosa. Graefes Arch Clin Exp Ophthalmol. 2013;251(6):1501-6.
Sudhalkar A, Kodjikian L, Borse N. Intravitreal dexamethasone implant for recalcitrant cystoid macular edema secondary to retinitis pigmentosa: a pilot study. Graefes Arch Clin Exp Ophthalmol. 2017;255(7):1369-74.
Valente EM, Silhavy JL, Brancati F, et al. Mutations in CEP290, which encodes a centrosomal protein, cause pleiotropic forms of Joubert syndrome. Nat Genet. 2006;38:623.
Vithana EN, Abu-Safieh L, Pelosini L, et al. Expression of PRPF31 mRNA in patients with autosomal dominant retinitis pigmentosa: a molecular clue for incomplete penetrance? Invest Ophthalmol Vis Sci. 2003;44:4204-4209.
Weiland J, Fink W, Humayun M, et al. Progress towards a high-resolution retinal prosthesis. Conf Proc IEEE Eng Med Biol Soc. 2005;7:7373-7375.
Wheeler L, WoldeMussie E, Lai R. Role of alpha-2 agonists in neuroprotection. Surv Ophthalmol. 2003;48 Suppl 1:S47-51.
Weleber RG, Kurz DE, Trzupek KM. Treatment of retinal and choroidal degenerations and dystrophies: current status and prospects for gene-based therapy. Ophthalmol Clin North Am. 2003;16:583-593, vii.
Yanai D, Weiland JD, Mahadevappa M, et al. Visual performance using a retinal prosthesis in three subjects with retinitis pigmentosa. Am J Ophthalmol. 2007;143:820-827.
Zito H, Downes SM, Patel RJ, et al. RPGR mutation associated with retinitis pigmentosa, impaired hearing and sino-respiratory infections. J Med Genet. 2003;40:609-615.
Online Mendelian Inheritance in Man (OMIM)
The information in NORD’s Rare Disease Database is for educational purposes only and is not intended to replace the advice of a physician or other qualified medical professional.
The content of the website and databases of the National Organization for Rare Disorders (NORD) is copyrighted and may not be reproduced, copied, downloaded or disseminated, in any way, for any commercial or public purpose, without prior written authorization and approval from NORD. Individuals may print one hard copy of an individual disease for personal use, provided that content is unmodified and includes NORD’s copyright.
National Organization for Rare Disorders (NORD)
55 Kenosia Ave., Danbury CT 06810 • (203)744-0100