Inherited Retinal Diseases for the Retina Specialist: Where to Start What can a clinician who is not an inherited retinal disease expert do for patients with these conditions? Start here. BY DANIEL L. CHAO, MD, PHD he maturation of gene therapy You can try to schedule these patients mon to order a panel of approximately has changed the paradigm of at the end of clinic or on another day 270 genes that have been implicated in inherited retinal diseases (IRDs) that is conducive to longer visits, or retinal degenerations in which a genetic from a diagnostic field to one you can refer such patients to a clinic cause of the disease is found in about in which promising therapies that specializes in IRDs. 50% of patients.1 This type of testing mayT be able to prevent blindness in Gene-based classification of IRDs can give patients a definitive diagnosis, patients with IRDs in the future. It is is becoming the norm, replacing the which can be a great relief, and can also important for every retina specialist previous nomenclature based on fun- help physicians identify patients for to educate himself or herself about dus findings. Lower costs have made potential enrollment in clinical trials. these diseases and about what new DNA sequencing more accessible to There are a number of ways to treatments or diagnostics might the general public, and genetic testing arrange for genetic testing. One is be available for these patients. This is becoming the standard of care for through the Foundation Fighting article presents several things retina patients with IRDs. This can include Blindness My Retina Tracker por- specialists should know about IRDs. single-gene testing if there is strong tal (see sidebar Foundation Fighting suspicion for a particular disease (eg, Blindness: Funding IRD Therapy A DIFFERENT APPROACH a mutation of RPE65 leading to Leber Research). Through this portal, patients Patients with IRDs require a dif- congenital amaurosis), but it is com- are entered into a registry that alerts ferent approach and workflow compared with patients with more typical diseases such as age-related AT A GLANCE macular degeneration and diabetic retinopathy. Careful history-taking is s In addition to the one approved gene therapy, there are more than important, and counseling the patient 30 ongoing middle- and late-stage clinical trials using gene therapy or about the diagnosis is a key part of the visit. This requires significant chair other molecular therapies for IRDs. time as these patients have likely s been told previously by other provid- Specialized IRD clinics can serve as one-stop shops for the needs of ers that they will go blind and that patients with IRDs. there are no treatments available. s Addressing patients’ psychologi- Support groups and online patient communities sometimes have as great cal concerns about the diagnosis is as an impact on a patient’s quality of life as any medical treatment. important as any medical treatment. JULY/AUGUST 2019 | RETINA TODAY 13 s RARE AND INHERITED DISEASES them to clinical trials for which they trials for specific IRDs, but clinical trials may qualify and can receive free com- for IRDs are dynamic and constantly mercial genetic testing with counseling. changing. The best way to find an RETINA TODAY Alternatively, commercial appropriate trial is to directly contact ON THE ROAD CLIA-certified laboratories such as retina specialists at centers that are par- Blueprint Genetics and GeneDx now ticipating in many of these clinical trials This article is adapted from a lecture the offer relatively affordable genetic testing to learn the latest updates. author presented in April at the Annual for retinal diseases. In general, insurance Vit-Buckle Society Meeting. The next only partially covers the costs of these CLINICAL CARE FOR PATIENTS WITH IRDS meeting will be held March 26-28, 2020, tests; out-of-pocket expense may range There is no consensus on nutri- from $500 to $2,000. tional supplementation for IRDs, in Miami. Visit VitBuckleSociety.org and although a healthy balanced diet is MedConfs.com for details. GENETIC COUNSELING recommended. Vitamin A should be Although technology now allows avoided by patients with Best disease high-dose vitamin A (15,000 IU) and us to perform sequencing rapidly, the or the cone-rod dystrophy Stargardt carotenoids has shown a modest effect interpretation of these tests to iden- disease, as vitamin A may exacerbate with decreased vision loss in patients tify a causative mutation is not always these diseases due to increased toxicity with retinitis pigmentosa, but the com- straightforward. Many times, there are through the visual cycle. bination is currently not recommended mutations in multiple genes that are A number of studies have investigated given equivocal efficacy, hepatotoxicity, predicted to cause changes in a protein, whether nutritional supplements such and other side effects. but these mutations have not been as high-dose vitamin A, docosahexae- How should a clinician who is not determined to cause a deleterious effect noic acid, lutein, and beta carotene can an IRD expert work up a patient responsible for the disease. These muta- prevent progression of vision loss in with an IRD? Currently, the standard tions are termed variants of unknown patients with IRDs.2 A combination of (Continued on page 23) significance. Additionally, the phenotype may be caused by a compound hetero- FOUNDATION FIGHTING BLINDNESS: zygous mutation, meaning heterozygous mutations in two separate genes. FUNDING IRD THERAPY RESEARCH Because of this complexity, it can be The Foundation Fighting Blindness, the world’s leading private funding source for inherited extremely helpful for genetic counsel- ors to discuss findings with patients. retinal disease (IRD) research, has raised more than $750 million toward its mission. The Genetic counselors who have special- nonprofit’s portfolio currently consists of 75 projects, including emerging gene, stem-cell, ized training in interpreting these tests and small-molecule therapies. Through its global My Retina Tracker patient registry, the can explain the findings to patients, Foundation is conducting a no-cost genetic testing study. Approximately 5,000 patients with freeing up the retina specialist for other IRDs have participated in the program. aspects of patient care. Retina specialists who do not have In 2018, the Foundation established its Retinal Degeneration (RD) Fund, a venture philan- easy access to a genetic counselor can thropy fund for emerging IRD therapies in the translational stage or undergoing evaluation consider using third-party genetic coun- seling groups such as InformedDNA. in early clinical trials. With more than $70 million under management, the RD Fund’s publicly disclosed projects include: FINDING TRIALS The US FDA approval of the first s Nacuity: A Dallas-based startup developing n-acetylcysteine amide, a small molecule gene therapy has ushered in a new era targeting oxidative stress in patients with retinitis pigmentosa and potentially other IRDs. in the treatment of IRDs. In addition to s SparingVision: A Paris-based company developing rod-derived cone viability factor, a voretigene neparvovec-rzyl (Luxturna, neuroprotective gene therapy for IRDs including retinitis pigmentosa. Spark Therapeutics), there are more s ProQR: An RNA therapeutics biotech developing antisense oligonucleotides for a broad than 30 middle- and late-stage clini- cal trials ongoing using gene therapy range of IRD genes including USH2A (exon 13 mutations) and Leber congenital amaurosis or other molecular therapies for IRDs, 10 caused by a CEP290 mutation. some with encouraging results. Resources such as clinicaltrials.gov Visit FightingBlindness.org and RetinalDegenerationFund.com to learn more. can be useful when searching for clinical 14 RETINA TODAY | JULY/AUGUST 2019 One Year in: Perspectives on Voretigene Looking back at the first year of the first ocular gene therapy. BY AARON NAGIEL, MD, PHD or novel therapeutic agents, period are eagerly awaited. In this course of disease would fare better, the first few years of use in the article, I review in general terms our young children benefit dramatically real world can occasionally raise center’s experience with the treatment through enrichment of their social, concerns that did not come to and highlight two areas in which our motor, and cognitive development. light during tightly controlled approach has evolved: patient selec- Improvements in eye contact, con- Fclinical trials.1 How has voretigene tion and surgical delivery. fidence in locomotion, and ability neparvovec-rzyl (Luxturna, Spark to read, play, and eat in normal or Therapeutics) fared in the 15 months PATIENT SELECTION dim lighting have enormous lifelong since treatment centers began admin- At Children’s Hospital Los Angeles, consequences and should not be istering it to patients with Leber con- we have treated nine children and underestimated. This highlights the genital amaurosis (LCA) caused by five adults bilaterally (28 eyes), and importance of early genetic testing biallelic mutations in RPE65? I believe the greatest benefits will and treatment, perhaps in patients as To be fair, its current use is not be observed with early treatment young as 1 year old. exactly “real world” in the sense that in childhood. Demonstrating these improve- any physician with the appropriate Although it is not surprising ments in a rigorous fashion in training can provide the treatment. that patients treated earlier in the young children