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; Oleg Alekseev, MD, PhD, Inherited Retinal Degenerations and Ophthalmic Genetic Diseases Fellow, Duke Eye Center; and Emily Krauss, MS, GC, Ophthalmic Genetic Counselor, Duke Eye Center, 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 so-called inherited retinal diseases, or IRDs), the light sensitive membrane that coats the inside of the eyes. Peripheral (or side) vision gradually decreases and eventually is lost in most patients. 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 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 in an autosomal recessive, autosomal dominant or X-linked recessive pattern. Maternally inherited variants of RP transmitted via the mitochondrial DNA also exist.
About half of all RP cases are isolated (these patients have no family history of the condition). This does not mean that the condition is not genetic (see below). 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 who 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”. Regardless of the severity, if any, of the disease expression in these patients, they remain capable of passing the genetic mutation to their own children, who can be fully affected. Examples of this scenario are the RP11 gene (PRPF31) and other genes of this family (e.g., PRPF8), which cause autosomal dominant RP and are especially prone to experiencing the “incomplete penetrance” phenomenon, which poses a significant diagnostic, prognostic and reproductive risk assessment challenge. However, 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 and cannot pass it on.
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 to 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. A child born to 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 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 X-linked RP 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 25% chance with each pregnancy of having a carrier daughter, a 25% chance of having a non-carrier daughter, a 25% chance of having a son affected with the disease, and a 25% 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 316 distinct genes mapped (that is, their approximate location on one of the chromosomes has been identified) and over 280 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 330 million in the United States in February 2021 (see http://www.census.gov for continuous updates), about 82,500 to 110,000 people in the United States have RP or a related disorder. With a worldwide population presently estimated at over 7.74 billion, it can be estimated that approximately 1.94 to 2.58 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 full-field flash electroretinography (ffERG) 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 and is essential 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 necessarily a substitute for vitamin A palmitate. The study results also indicated that taking 400 IU daily of vitamin E supplementation did not delay retinal disease progression but in fact hastened it, whereby RP patients are generally 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 or other bone fractures. In these patients, it may be wise to obtain a baseline bone density scan and, in the presence of existing osteoporosis, treat the underlying disorder appropriately 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 recently been formally studied retrospectively also in children followed by at the Massachusetts Eye and Ear Infirmary. The study included 55 children with different genetic types of RP taking vitamin A palmitate and 25 not taking vitamin A. Age-adjusted dosage supplementation were given to the children (5,000 IU/day for ages 6-10 years old, 10,000 IU/day for ages 10-15 years old, and 15,000 IU/d for ages ≥15 years old, provided that the children had normal serum liver function test results at baseline). Parents were advised that their children taking vitamin A should eat a regular diet, avoid a high-dose vitamin E supplement, monitor their serum liver function annually and return to clinic for follow-up assessment and possible dose adjustment every 2 years. No adverse effects were reported in any of the children on these vitamin A palmitate dose ranges. While this was a retrospective investigation, and not a formal, randomized prospective trial, similar to what reported previously in adults, the cone ERG responses of children on these supplementation regimens on average declined less than those who were not, supporting further the notion that this supplementation regimen may be beneficial in reducing the overall rates of disease progression also in children. Thus, this evidence of supplement efficacy and safety suggests that also children with RP should consider oral supplementation of vitamin A palmitate with age-adjusted dosage under the care of their pediatrician.
Furthermore, it should be noted that 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. Also, long term use of DHA supplements was not associated with benefits. Therefore, DHA supplementation beyond 2 years from its onset according to the criteria summarized above is not recommended, except for X-linked RP (see below).
Additional studies from the same group have subsequently reported further reduction in the rate of visual field sensitivity loss in RP patients who took 12 mg of daily lutein added to the previously studied 15,000 IU vitamin A palmitate supplementation regimen compared to those on vitamin A alone.
Another relevant trial was a specific one focused 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, which was based on preexisting evidence that there is an abnormality in fatty acid metabolism in XLRP patients leading up to an impaired DHA synthesis, tested the potential benefits of a higher dose of DHA than that previously tested on this specific type of RP. The results did not show a statistically significant reduction in loss of electroretinographic function as compared with placebo. However there was a significant reduction in the rates of visual field loss in the DHA treated group. Therefore, high-dose DHA supplementation is recommended in patients with X-linked RP.
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.
Tauroursodeoxycholic acid (TUDCA), a major component of bear bile, is another supplement that has come to light as a photoreceptor-protective agent for use in RP. Interestingly, an alternate version of the bile acid pathway has now been demonstrated to be important for cholesterol metabolism in the retina. Bile acids appear to activate several types of molecular signaling receptors within the retina. In several different animal models of RP, TUDCA was demonstrated to significantly slow down the rate of disease progression, as evidenced by preserved retinal anatomy and electrophysiological function. Systemic administration of TUDCA was shown to reduce cellular stress and preserve photoreceptors in several models of RP, including Leber congenital amaurosis and RP associated with RPGR and PDE6B mutations, as well in animal models of the syndromic form of RP, known as Bardet-Biedl syndrome. Furthermore, in these models, TUDCA also prevented/reduced obesity, a disease feature that is otherwise notoriously challenging to address. TUDCA is available as an over-the-counter supplement. Human trials in conditions other than RP have utilized safely a 500 mg daily dosage. It is not exactly known whether this oral dosage would be effective in RP. Of note, there is now an FDA approved drug to reduce obesity in Bardet-Biedl syndrome and other related ciliopathies, called setmelatonide that tackles a specific mechanism that is at play in these forms of syndromic obesity.
Interestingly, saffron, a spice derived from the flower of Crocus sativus, has gained interest in recent years as well, after animal studies demonstrated beneficial effects in neurodegenerative diseases and RP. Safranal (which contains crocin and crocetin) is thought to be the active chemical component of saffron that is responsible for this neuroprotective effect. A human trial of a highly purified 20 mg saffron supplement in macular degeneration indicated beneficial effects on macular function, and a trial of a macular dystrophy, Stargardt disease, suggested similar benefits. To our knowledge, to date no formal RP trial of saffron supplementation has been conducted. However, the neuroprotective potential of saffron appears to be gene- and disease type-independent, and therefore it is likely to apply also to RP.
Another emerging supplement for use by RP patients is N-acetylcysteine (NAC), discussed in the “Antioxidants” section below.
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 to ophthalmologists in the clinical setting, 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 in 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 increases the risk of other complications, such as glaucoma or cataract, and a very 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 normally 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 implants have 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 100 mg 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). 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. Most modern smart phone devices have the “dark mode” feature that limits the total light exposure of the retina while maintaining good contrast level.
Genetic counseling is also recommended for affected individuals and their families.
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 – a 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 or 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 was the FDA approval of the first ocular gene therapy drug, Luxturna. This success is the outcome of three independent human clinical trials of gene therapy for LCA caused specifically by RPE65 gene mutations. Participants in these trials were 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. This incredibly encouraging development has opened 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, the development of a gene therapy for each particular gene underlying RP disease will be necessary, as well as clinical trial testing of these new therapies for safety and efficacy. Furthermore, detailed natural history studies of the numerous RP subtypes will be necessary 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.
In the meantime, numerous promising clinical trials of novel gene therapies for RP are underway for X-linked RP linked to mutations in the RPGR gene, some dominant and recessive forms of RP, some subtypes of LCA, as well related conditions such as Usher syndrome type 2A and choroideremia. The relatively recent advent of the CRISPR/Cas9 gene editing system has brought closer to life the possibility of treating not only some forms of LCA but also dominant forms of RP, a challenge that to date has not been possible to address with conventional gene therapy (gene replacement therapy). This approach too is in trials and is currently being further optimized for safety and efficacy.
Reviewing all the ongoing trials here in detail is beyond the scope of this chapter. At this point in time, new trials are added to the list constantly and interested readers can consult www.clinicaltrials.gov or contact the organizations listed below for updates.
It is important to understand that gene therapy proper, meaning an approach aimed at correcting a genetic defect, is possible only in patients whose disease genetic cause has been discovered. Thus, all patients affected with RP are urged to undergo genetic testing in an effort to discover the genetic cause to their condition. This is a necessary initial step to open the doors of gene therapy to all patients. Even in patients who may be outside of the therapeutic window for their particular gene, knowing the causal gene remains very important, since this will confirm the diagnosis of RP beyond any reasonable doubt (this in itself is very important, since there are also conditions that can simulate RP that have a different etiology) and will allow IRD specialists to determine if gene therapy or other approaches may be better suited as a treatment based on the clinical and functional disease characteristics and stage of any given individual patient.
Presently, gene therapy is possible for only a relatively small subset of 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 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 and permit correct reproductive risk assessment, 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 who 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, known as translational read-through drugs. This type of approach 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 particular 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 suggested that RP patients with genetic mutations affecting the folding of the encoded protein may benefit from VPA. Unfortunately, a phase II trial of VPA in patients with dominant RP (ClinicalTrials.gov identifier: NCT01233609) has shown no visual benefit of VPA, and in fact, patients on VPA supplementation showed worse visual field preservation than the control group. However, a similar effect (and an improved degradation of the misfolded proteins inside the retinal cells) has been recently shown to occur when cells are treated in a laboratory setting with an anti-metabolite drug known as methotrexate (MTX), a well-known safe drug that is commonly used for cancer and autoimmune disease management. Intravitreal MTX has been shown to be effective in certain animal models of RP, whereby an intravitreal formulation of MTX has very recently been granted permission by the FDA for testing in humans with forms of RP in which this molecular mechanism is believed to be at play.
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 and RPE65 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. Further developments to this effect are awaited.
d) mRNA editing: Another approach that is gene-specific, and in fact aims at treating diseases at an even more granular level (mutation- or exon-specific), but that does not change the gene itself, but alters its abnormal byproduct before it is converted into the protein that the gene encodes is mRNA editing. Genes are initially transcribed into mRNA, which in turn is translated into a protein. By editing the mRNA prior to translation, the protein produced by the gene can be corrected to produce a fully functional protein or it can be otherwise altered to yield a better functioning protein than the original mutated and, thus, defective one. By utilizing this approach, there have already been robust initial signs of efficacy in both LCA and IRDs linked to mutations in exon 13 of the USH2A gene, and phase 3 trials are underway to confirm the initially positive results.
The specificity of this approach is, at this time, also a limitation, since it cannot be presently used to correct a whole-gene defect, and it has efficacy that is limited in time, since new copies of abnormal mRNA continue to be made by the defective gene requiring frequent re-editing. However, the latter limitation can be overcome with repeated, serial treatments, whereby this treatment method remains very promising and is being further explored to treat additional conditions.
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 has been 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 eyeball 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, was successfully completed.
CNTF phase II/III clinical trials of RP with this special proprietary device at a dozen different sites across the United States have been completed: the CNTF3 trial was 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. 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 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 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. 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 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 certain imaging outcomes to standard and widely accepted visual function outcomes such as visual acuity and visual fields.
One completed study is that of a micro-implant, called posterior segment drug delivery system that is injected inside the vitreal chamber of the eyeball. This device was 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 many 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 may open 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 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.
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. Recently, a phase 1 clinical trial of oral N-acetylcysteine (NAC) carried out at Johns Hopkins University has demonstrated significant improvement in visual acuity and macular sensitivity in RP patients taking oral NAC supplementation (NCT03063021) for 6 months. NAC is a scavenger of reactive oxygen species and is, therefore, thought to protect cone photoreceptors from the oxidative stress generated by the demise of rod photoreceptors. An extension trial is currently underway (NCT03999021) to further evaluate the safety and efficacy of NAC in RP patients after 2 years of supplementation, and a subsequent phase 2/3 trial has been planned for the near future. Also underway is a trial of a modified form of NAC called NACA (NCT04355689).
Recombinant Human Nerve Growth Factor (hNGF)
A completed randomized clinical trial (ClinicalTrials.gov identifier: NCT02609165) investigated 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.
Rod-Derived Cone Viability Factor (RdCVF)
Researchers have identified a protein that preserves cone photoreceptors. A gene therapy has been designed to express this protein, named rod-derived cone viability factor, or RdCVF. The goal of the treatment is to preserve cone cells in patients with RP, Usher syndrome, and other related conditions. A clinical trial of the RdCVF gene therapy is planned to launch in the near future.
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 are not yet publicly available.
Human Retinal Progenitor Cells
There are currently several ongoing clinical trials testing the safety of injection of human retinal progenitor cells (hRPC) in RP. Early results have been promising and some of these studies are in phases 1/2 and 2. Results are expected within the next few years. To enhance the survival and functionality of transplanted stem cells in the retina, the idea of retinal sheet transplantation has been developed and has shown promise in animal models. In this approach, human fetal retinal tissue is implanted as a sheet into an RP retina. Modern technology allows also for laboratory differentiation of a 3-dimensional retina from progenitor cells. This methodology has shown positive outcomes in retinal sheet transplantation in several different animal models of RP and thus may represent a feasible treatment strategy in the future.
As a note of caution, there is evidence of severe visual loss including complete blindness after ocular intravitreal injection of autologous adipose derived “stem cells” from an unregulated clinic in the United States, which, to the best of our knowledge, has now been impeded from further promoting this treatment of unproven efficacy and safety. At this time, it remains of utmost importance to wait for the results of formal, rigorous clinical trials that test the safety and efficacy of these new treatments before undergoing any such treatment.
Intravitreal Injection of hRPC
A conceptually similar way to utilize live fetal stem cells is to inject them into the vitreous chamber of the eye (NCT02320812). In this case, the injected stem cells are used as a source for growth factors that are spontaneously secreted by these stem cells. The release of these growth factors promotes improved health of the existing, remaining retinal cells. A rigorous phase 1/2 trial has been successfully completed, meeting both safety and efficacy endpoints, and a phase 3 trial utilizing this approach is imminent. In this case, unlike the approaches that aim to transplant stem cell, it is important to understand that these injected stem cells trials aim to improve the health of the remaining retinal cells, but not to restore vision in areas where vision has already been completely lost.
Endogenous Stem Cell Stimulation
One last approach regarding stem cells is the stimulation to proliferate the ones we have in our own eyes, but that, normally in humans and in most mammals, rest in the dormant state at the very edge of the far peripheral retina. The discovery of these stem cells in the human eye was made over 20 years ago, but it was not until recently that a cocktail of stimulating factors that appears to be capable of awakening our dormant stem cells was discovered and perfected. When repeatedly injected in the eyes of mice with RP, this cocktail was effective at stimulating the dormant stem cells to proliferate and migrate from the periphery of the retina towards the posterior pole and restored significant vision in the treated animals. If confirmed safe and effective also in humans, this approach should permit on paper partial peripheral vision restoration and ability to detect light in areas previously devoid of vision due to the advancement of the retinal degenerative damage caused by RP. It is theoretically possible that these endogenous stem cells may also release in the subretinal space growth factors that improve the health of the existing, remaining retinal cells, whereby their health too may improve. To test these possibilities, a phase 1/2 human trial is imminent (NCT04763369).
One important distinctive aspect of this approach is that the stem cells in question are the ones of the very patient, thereby not requiring any transplantation or utilization of external sources of cells of any type (which, in turn, usually requires some degree of immunosuppression like with any other organ or cell transplant). This represents a theoretical advantage but may also be a potential disadvantage. The latter is due to the fact that one’s own stem cells, albeit healthier than the degenerated original retinal cells, will still contain the same genetic abnormalities that led retinal cells to degenerate in first place. Thus, the benefit of this treatment may potentially be limited in time. However, if this approach will be confirmed to be both safe and effective, one can envision that it may be possible to overcome this inherent potential limitation of this method by injecting the “stimulating cocktail” repeatedly if not indefinitely over time, or even provided on a long-term basis via slow-release implants placed in the eye.
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 ischemic optic neuropathy or longstanding retinal artery occlusion. A 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 one of proven efficacy.
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 are published in 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 and 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. Rehabilitative measures after receiving this implant are necessary to learn how to benefit from the Argus II implant and to receive the full benefits of this device. The Argus II device had been FDA-approved, but has now been discontinued.
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.
In a more recent development, Second Sight Medical Products, Inc. (Los Angeles, CA) received FDA approval for the Argus 2s Retinal Prosthesis System in March 2021. This system is believed to be a significant advance compared to its predecessor, Argus II, as it offers ergonomic improvements, more processing power, and enhanced video processing. It is expected to be used with the next generation Orion Visual Cortical Prosthesis System currently under development.
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 themselves, which normally have limited light sensing capabilities on their own. If transfected with one of these synthetic, algae-derived genes (channelrhsodopsin-2 or halorhodopsin, and modifications thereof), 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 several optogenetics clinical trials are currently underway. 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 synthetic versions of these algae genes are artificially implanted into the retina, but no physical device actually needs to be implanted. As such, this artificial vision restorative approach represents a true hybrid with gene therapy (which normally aims to restore a defective or lost gene function instead in the photoreceptor cells of the retina, which are the usually ones directly affected by the problem).
There is now initial evidence of efficacy for this treatment approach that has been published, paving the way for likely larger scale human trials. It is possible that, if this approach is proven further to be both safe and effective, additional developments may extend to less severe stages of RP and perhaps also to other conditions, such as CORD and macular dystrophies such as Stargardt disease. This is in part because, to date, this treatment, which at this time is delivered by intravitreal injection and not underneath the retina, tends to concentrate itself spontaneously to the macular region. While this may represent a limitation if trying to give back peripheral vision to patients, it may prove to be an advantage in conditions where the majority of the damage may be concentrated in the macular region – or even if forms of RP that may be complicated further by damage to the macular structures as well (so called “macular atrophy”).
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: https://rarediseases.org/for-patients-and-families/information-resources/info-clinical-trials-and-research-studies/
For information about clinical trials sponsored by private sources, contact: www.centerwatch.com
For information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/
Contact for additional information about retinitis pigmentosa:
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, 2351 Erwin Road, DUMC Box 3802 Durham, NC 27710
Clinic & Diagnostic Lab Coordinator: (919) 684-1857
Email: [email protected]
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