NORD gratefully acknowledges Alessandro Iannaccone, MD, MS, Associate Professor of Ophthalmology, Director, Retinal Degeneration & Ophthalmic Genetics Service and Lions Visual Function Diagnostic Lab, University of Tennessee Health Science Center, Hamilton Eye Institute, 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 also 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.
Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22, and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome, and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many numbered bands. For example, “chromosome 11p13” refers to band 13 on the short arm of chromosome 11. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
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 resulting 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 (“mutated”), 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 defective 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 from both parents and is both healthy and genetically entirely normal for that particular trait is also 25%. The risk of manifesting an autosomal recessive disorder is normally the same for males and females. All children born of a person affected with an autosomal recessive condition will receive one copy of the defective 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 nearly 314 million in the United States in mid-July 2012 (see < http://www.census.gov/> for continuous updates), about 78,500 to 105,000 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 and visual field testing. 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, since an adverse interaction between smoking and beta-carotene has been documented, whereby smokers of 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 very 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 exact dosage to be given to children with RP is not 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 naïve 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.
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. Therefore, this approach should be used only as a second line treatment in RP until formal trials of the efficacy of these treatments are conducted. Periocular injections pose a much lower risk of glaucoma and cataracts, and do not pose a risk of endophthalmitis. A new formulation of one such medication specifically designed for intravitreal injection has recently become available, but has yet to be tried in patients with RP.
For individuals with RP, low-vision aids and other assistive devices may be of benefit as vision worsens. 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.
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 “good” 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.
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. Other human, Phase I/II gene therapy trials are presently ongoing for choroideremia, which is also X-linked (ClinicalTrials.gov identifier: NCT01461213), for ABCA4-linked recessive Stargardt macular dystrophy (ClinicalTrials.gov identifier: NCT01367444), 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 disorders 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-independent or gene-specific ones.
Gene-independent therapies are aimed at providing benefit to retinal health across the board, regardless of the genetic cause. Nutritional treatments like vitamin A palmitate and lutein fall in this category. Other such examples include:
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.
Argus II. 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: NCTNCT00407602). Preliminary results have been reported and appear very encouraging, although technological development of the implants and long-term monitoring of the patients who received the implants (ClinicalTrials.gov identifier: NCT01490827) remain in progress.
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 recently completed and results of this experimental approach remain pending.
Stem cells. Trials of this promising treatment option are not yet being performed for RP. However, some trials that utilize embryonic stem cell-derived pigment epithelial cells are ongoing for Stargardt macular dystrophy (ClinicalTrials.gov identifier: NCT01505062 and NCT01345006). Results are expected within the next few years.
Supplementation. Another ongoing trial is a specific one of DHA supplementation in children and young adults with X-linked RP, which is being conducted at the Retina Foundation of the Southwest (ClinicalTrials.gov identifier: NCT00100230). This trial is testing the potential benefits of a higher dose of DHA than that previously tested on the same type of RP, with results trending toward possible efficacy but inconclusive as to whether DHA alone would be effective in slowing down disease progression. Results of this trial will become known within the next few years.
Posterior Segment Drug Delivery Systems. Lastly, one more Phase I/II trial that is presently ongoing and open for enrollment 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 are being 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 are pending.
Gene-specific therapies. Like for gene therapy, to benefit from these treatments, patients need to know the specific genetic cause of their individual disease. Molecular genetic diagnostic testing is nowadays 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. Such type of drug is being currently 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 so long as they have their diseases harbored 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 type of drugs 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 is presently being conducted on patients with dominant RP (ClinicalTrials.gov identifier: NCT01233609) and will have a follow up of at least one year. 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 molecule 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 improve significantly their visual field. For this reason, two trials of QLT091001 are presently ongoing (ClinicalTrials.gov identifiers: NCT01014052 and NCT01521793).
In addition, the Foundation Fighting Blindness lists a brief 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
For information about clinical trials sponsored by private sources, contact:
Contact for additional information about retinitis pigmentosa:
Alessandro Iannaccone, M.D., M.S.
Associate Professor of Ophthalmology
Director, Retinal Degeneration & Ophthalmic Genetics Service
and Lions Visual Function Diagnostic Lab
President, Foundation Fighting Blindness Mid-South Chapter of Memphis
Scientific Advisory Board Member, Foundation Fighting Blindness
University of Tennessee Health Science Center
Hamilton Eye Institute
930 Madison Ave., Ste. 731 (research)/Ste. 400 (clinic)
Memphis, TN 38163
Clinic & Diagnostic Lab: (901) 448-5026
Clinical Research Coordinator: (901) 448-6445
Fax: (901) 448-5028
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.
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.
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.
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.
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.
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.
Loktev AV, Zhang Q, Beck JS, et al. A BBSome subunit links ciliogenesis, microtubule stability, and acetylation. Dev Cell. 2008;15:854-865.
Nachury MV. Tandem affinity purification of the BBSome, a critical regulator of Rab8 in ciliogenesis. Methods Enzymol. 2008;439:501-513.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Ghajarnia M, Gorin MB. Acetazolamide in the treatment of X-linked retinoschisis maculopathy. Arch Ophthalmol. 2007;125:571-573.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Apushkin MA, Fishman GA. Use of dorzolamide for patients with X-linked retinoschisis. Retina. 2006;26:741-745.
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.
Kim JE. Intravitreal triamcinolone acetonide for treatment of cystoid macular edema associated with retinitis pigmentosa. Retina. 2006;26:1094-1096.
Sandberg MA, Gaudio AR, Berson EL. Disease course of patients with pericentral retinitis pigmentosa. Am J Ophthalmol. 2005;140:100-106.
Iannaccone A. The genetics of hereditary retinopathies and optic neuropathies. Comp Ophthalmol Update. 2005;5:39-62.
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.
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.
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.
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.
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.
Genaro Pde S, Martini LA. Vitamin A supplementation and risk of skeletal fracture. Nutr Rev. 2004;62:65-67.
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.
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. Further evaluation of docosahexaenoic acid in patients with retinitis pigmentosa receiving vitamin A treatment: subgroup analyses. Arch Ophthalmol. 2004;122:1306-1314.
Iannaccone A, Wang X, Jablonski MM, et al. Increasing evidence for syndromic phenotypes associated with RPGR mutations. Am J Ophthalmol. 2004;137:785-786.
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.
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, Sarkisian SRJ, Kerr NC, Morris WR. The genetics of glaucoma, cataracts and corneal dystrophies. Comp Ophthalmol Update. 2004;5:307-326.
.Adamus G, Ren G, Weleber RG. Autoantibodies against retinal proteins in paraneoplastic and autoimmune retinopathy. BMC Ophthalmol. 2004;4:5.
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.
DiMauro S, Schon EA. Mitochondrial respiratory-chain diseases. N Engl J Med. 2003;348:2656-2668.
Chan JW. Paraneoplastic retinopathies and optic neuropathies. Surv Ophthalmol. 2003;48:12-38.
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.
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.
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.
Lee TK, McTaggart KE, Sieving PA, et al. Clinical diagnoses that overlap with choroideremia. Can J Ophthalmol. 2003;38:364-372; quiz 372.
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.
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.
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.
Is it true that too much vitamin A may increase my risk of bone fractures? Mayo Clin Womens Healthsource. 2003;7:8.
Lips P. Hypervitaminosis A and fractures. N Engl J Med. 2003;348:347-349.
133. Wheeler L, WoldeMussie E, Lai R. Role of alpha-2 agonists in neuroprotection. Surv Ophthalmol. 2003;48 Suppl 1:S47-51.
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.
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.
Feskanich D, Singh V, Willett WC, Colditz GA. Vitamin A intake and hip fractures among postmenopausal women. Jama. 2002;287:47-54.
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.
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.
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.
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.
Burke J, Schwartz M. Preclinical evaluation of brimonidine. Surv Ophthalmol 1996;41:S9-S18.
Online Mendelian Inheritance in Man (OMIM). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=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.