Inherited Retinal Diseases for the 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 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.

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(Continued on page (Continued

RETINA TODAY RETINA ON THE ROAD a lecture the This article is adapted from at the Annual author presented in April The next Vit-Buckle Society Meeting. 26-28, 2020, meeting will be held March and in Miami. Visit VitBuckleSociety.org MedConfs.com for details. How should a clinician who is notis who clinician a should How given equivocal efficacy, hepatotoxicity,efficacy, equivocal given effects. side other and patienta up work expert IRD an standardthe Currently, IRD? an with high-dose vitamin A (15,000 IU) andIU) (15,000 A vitamin high-dose effectmodest a shown has carotenoids patientsin loss vision decreased with com the but pigmentosa, retinitis with recommendednot currently is bination - - (exon 13 mutations) and Leber congenital amaurosis mutations) and Leber congenital amaurosis (exon 13 - USH2A mutation. A Paris-based company developing rod-derived cone viability factor, a a factor, cone viability rod-derived Paris-based company developing A A combination ofcombination A CEP290 2 A Dallas-based startup developing n-acetylcysteine amide, a small molecule a small molecule amide, n-acetylcysteine A Dallas-based startup developing An RNA therapeutics biotech developing antisense oligonucleotides for a broad RNA therapeutics biotech developing antisense oligonucleotides for a broad An SparingVision: including . IRDs neuroprotective gene therapy for ProQR: range of IRD genes including caused by a 10 Nacuity: stress in patients with retinitis pigmentosa and potentially other IRDs. targeting oxidative   s  s s Visit FightingBlindness.org and RetinalDegenerationFund.com to learn more. RetinalDegenerationFund.com to Visit FightingBlindness.org and thropy fund for emerging IRD therapies in the translational stage or undergoing evaluation evaluation or undergoing stage in the translational for emerging IRD therapies thropy fund publicly Fund’s the RD million under management, more than $70 With trials. early clinical in include: disclosed projects The Foundation Fighting Blindness, the world’s leading private funding source for inherited private funding source for inherited leading Fighting Blindness, the world’s Foundation The The its mission. more than $750 million toward retinal disease (IRD) research, has raised projects, including emerging gene, stem-cell, of 75 currently consists portfolio nonprofit’s registry, the My Retina Tracker patient therapies. Through its global small-molecule and with patients no-cost genetic testing study. Approximately 5,000 Foundation is conducting a the program. participated in IRDs have Degeneration (RD) Fund, a venture philan Retinal In 2018, the Foundation established its FOUNDATION FIGHTING BLINDNESS: FOUNDATION FIGHTING BLINDNESS: FUNDING IRD THERAPY RESEARCH A number of studies have investigated have studies of number A There is no consensus on nutri on consensus no is There recommended. Vitamin A should beshould A Vitamin recommended. diseaseBest with patients by avoided Stargardt dystrophy cone-rod the or exacerbatemay A vitamin as disease, toxicityincreased to due diseases these visualcycle. the through suchsupplements nutritional whether docosahexae A, vitamin high-dose as cancarotene beta and lutein, acid, noic inloss vision of progression prevent IRDs. with patients trials for specific IRDs, but clinical trials clinical but IRDs, specific for trials constantlyand dynamic are IRDs for an find to way best The changing. contactdirectly to is trial appropriate par are that centers at specialists retina trialsclinical theseof many in ticipating updates. latest the learn to WITH IRDS CLINICAL CARE FOR PATIENTS IRDs, for supplementation tional isdiet balanced healthy a although ------compound hetero compound variants of unknownof variants , meaning heterozygousmeaning , . Additionally, the phenotypethe Additionally, . | JULY/AUGUST 2019 | JULY/AUGUST

Resources such as clinicaltrials.govas such Resources The US FDA approval of the firstthe of approval FDA US The Retina specialists who do not havenot do who specialists Retina Because of this complexity, it can becan it complexity, this of Because Although technology now allowsnow technology Although Alternatively, commercialAlternatively, than 30 middle- and late-stage clini late-stage and middle- 30 than therapygene using ongoing trials cal IRDs,for therapies molecular other or results.encouraging with some clinicalfor searching when useful be can FINDING TRIALS FINDING TRIALS eranew a in ushered has therapy gene toaddition In IRDs. of treatment the in (Luxturna,neparvovec-rzyl voretigene moreare there Therapeutics), Spark freeing up the retina specialist for otherfor specialist retina the up freeing care.patient of aspects cancounselor genetic a to access easy coun genetic third-party using consider InformedDNA.as such groups seling extremely helpful for genetic counsel genetic for helpful extremely patients.with discussfindings to ors special have who counselors Genetic teststhese interpreting in training ized patients,to findings the explain can responsible for the disease. These muta These disease. the for responsible termed are tions significance a by caused be may mutation zygous genes. separate two in mutations interpretation of these tests to iden to tests these of interpretation alwaysnot is mutation causative a tify arethere times, Many straightforward. arethat genes multiple in mutations protein,a in changes cause to predicted beennot have mutations these but effectdeleterious a cause to determined tests; out-of-pocket expense may rangemay expense out-of-pocket tests; $2,000. to $500 from GENETIC COUNSELING therapidly, sequencing perform to us mercial genetic testing with counseling.with testing genetic mercial assuch laboratories CLIA-certified now GeneDx and Blueprint testinggenetic affordable relatively offer insurance general, In diseases. retinal for theseof costs the covers partially only them to clinical trials for which theywhich for trials clinical to them com free receive can and qualify may RETINA TODAY

14 RARE DISEASES INHERITED AND s 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 remains a challenge, Rather, since voretigene received approval by the US FDA, nine treat- ment centers have been designated across the United States, and each AT A GLANCE site has only a few (most have one s or two) surgeons cleared to provide At nine treatment centers across the United States, selected surgeons have the treatment. All treating physicians been designated to provide treatment with -rzyl. were required to undergo wet labora- tory training and to review in detail s In the first year after this gene therapy’s postapproval use, clinicians have the surgical manual put forth by the manufacturer of this ocular gene ther- refined their approaches to patient selection and surgical delivery.

apy, which is the first to be approved s by the FDA. The greatest benefit may be seen with treatment in early childhood for Formal analysis on 1-year outcomes RPE65-associated LCA. of voretigene in the postapproval

JULY/AUGUST 2019 | RETINA TODAY 21 - - mutations, triamcinolone is RPE65 For the first few surgeries wesurgeries few first the For Some of the fine points include theinclude points fine the of Some voreti of trials clinical the Because with ofpresence the confirming for helpful detachment. vitreous posterior a Bleb Creation manual’s surgical the to adhered traineda have to recommendation as manually vector the inject assistant following: Use of Triamcinolone useroutine the permit not did gene weintraoperatively, triamcinolone of Sincecase. first our during it avoided aidto cases all in it used have we then, vit the Because vitreous. of removal in patientsin syneretic be to tends reous - - - Figure. Intraoperative OCT-guided subretinal injection of voretigene neparvovec-rzyl in a pediatric patient. Figure. Intraoperative OCT-guided subretinal injection of Our surgical approach to the deliv the to approach surgical Our OR DEMONSTRATE THE EQUIVALENCE OF EQUIVALENCE OF OR DEMONSTRATE THE LEAVING THESE TO VARIOUS TECHNIQUES, INVESTIGATOR DISCRETION. AS WE AGGREGATE OUR DATA ACROSS DATA ACROSS AS WE AGGREGATE OUR IT MAY BE TREATMENT CENTERS, BEST PRACTICES POSSIBLE TO IDENTIFY ous techniques, leaving these to inves to these leaving techniques, ous discretion. tigator ery of voretigene has evolved since evolved has voretigene of ery March in treated we patient firstthe Therapeutics Spark Although 2018. training laboratory wet provided no are there manual, surgical a and the on rules procedural hard-and-fast allowed has This label. medication over evolve to center treatment each different slightly adopt and time data our aggregate we As approaches. be may it centers, treatment across or practices best identify to possible vari of equivalence the demonstrate pathogenicity before proceeding withproceeding before pathogenicity surgery. therapy gene SURGICAL DELIVERY ------

- in - - - - - , are, RPE65 variants vitro mutagen vitro

gene testing. This testing. gene RPE65 variants of uncertain signifi uncertain of variants | JULY/AUGUST 2019 | JULY/AUGUST

, or VUS, which means we are notare we means which VUS, or , (ie, on separate alleles).separate on (ie, Finally, when VUS arise, one shouldone arise, VUS when Finally, Panel-based testing should beshould testing Panel-based As a treating surgeon, I have the ulti the have I surgeon, treating a As If only it were that easy.that were it only If or mutations, Many Another aspect that may be under be may that aspect Another we test, especially when the evidencethe when especially test, we wanting.be may pathogenicity for in consider strongly toassays protein functional with esis mutationaldemonstrate definitively emphasized over single-gene testing totesting single-gene over emphasized genet landscapeof the see to us allow at“love a prevent and alterations ic associ we wherein scenario, sight” first geneonly and first the to causation ate regard. Furthermore, I require that thethat require I Furthermore, regard. candidatevoretigene every of parents undergo also crucialespecially is analysis segregation muta heterozygous compound for are they that demonstrate to tions trans mate responsibility to ensure the valid the ensure to responsibility mate subjecting before testing genetic of ity amI vitrectomies. bilateral to patient a bioinfor excellent have to fortunate pathologistsmolecular and maticists thisin me aid to institution my at to be pathogenic, even if they arethey if even pathogenic, be to areothers still And mutations. novel labeled cance effect.their of sure be obvious that mutations in mutations that obvious be LCA.cause tonot predicted are they and benign, proteinin alteration significant cause predictedare variants Some function. lar pathology or bioinformatics. Ourbioinformatics. or pathology lar ophthalmologistsas training clinical the over glosses specialists retina and weas testing genetic of intricacies withgenes of names associate to come shouldit now, By conditions. certain come measures such as light sensitiv light as such measures come fields. visual or testing ity ofcomplexity the is appreciated Althoughtesting. diagnostic molecular doI background, scientific a have I molecu in training formal have not however, because these patients may patients these because however, out standard with cooperate not RETINA TODAY

22 RARE DISEASES INHERITED AND s RARE AND INHERITED DISEASES s

the primary surgeon positioned the subretinal cannula. We (Continued from page 14) moved on to using the MicroDose Injection Kit (MedOne workup to diagnose and follow patients includes a standard Surgical) to allow autonomous control of the subretinal ophthalmic examination with fundus photos, fundus auto- injection by the primary surgeon. This has been a fantastic fluorescence, and OCT imaging. Genetic testing can be con- improvement. We proceed directly with injection of the vec- sidered. Additional workup that is not common in the retina tor without first creating a saline “prebleb.” clinic may include periodic kinetic perimetry (eg, Goldman or automated kinetic perimetry) and electroretinography, OCT Guidance which may be done at a more specialized IRD clinic. Although it is not essential, the use of OCT intraopera- IRD centers can serve as one-stop shops for the needs of tively has been a great visual aid for determining the location patients with IRDs. IRD specialists can provide specialized of the bleb and status of the fovea. I deliver the vector with workups, an infrastructure for genetic testing and counsel- the two-line crosshair overlay on the ReScan microscope ing, and access to the latest clinical trials and research. (Carl Zeiss Meditec; Figure). This has allowed me to better understand the importance of cannula positioning and to NONCLINICAL RESOURCES characterize some atypical bleb appearances (eg, schisis at Patient communities and online groups are invaluable the edge of the bleb). for patients with IRDs. As noted previously, many of these patients have been told that they will go blind and that Air-Fluid Exchange there is no treatment available, which can have significant We routinely perform a complete air-fluid exchange, as psychological and functional effects on patients. Patient recommended in the surgical manual. The idea is to tam- advocacy groups and foundations provide excellent venues ponade the retinotomy and limit extravasation of potentially for patients to support each other, and such support can inflammatory vector into the vitreous cavity, but I am not have a dramatic effect on patients’ quality of life. The larg- sure if this step is necessary. est of these is the Foundation Fighting Blindness. The foun- dation has many local chapters across the United States. SUMMARY Additionally, online communities such as Facebook groups It is an extraordinary privilege to be able to deliver this can be helpful. I recommend referring patients to these unique treatment to our patients. I am hopeful that the col- groups because, many times, this support can have as great lective outcomes from our nine centers will buttress the find- of a significance on quality of life as any medical treatment. ings of the phase 3 trial2 and support continued enthusiasm for voretigene in the treatment of this previously incurable HOPE FOR THE FUTURE form of blindness. A multidisciplinary approach is important when treating We all must recall the grit and dedication of individuals patients with IRDs. Given the complicated nature of care such as Michael Redmond, PhD; Jean Bennett, MD, PhD; for these patients, such a multidisciplinary team should Albert M. Maguire, MD; and many more, and the fund- include a retina specialist, preferably with some training in ing sources that made the investigation and approval of IRDs; a genetic counselor; a low-vision specialist; and social this novel gene therapy possible. Ideally, our early clini- workers. All of these individuals play essential roles in mak- cal real-world experience with voretigene will serve as a ing sure these patients are taken care of at all levels. blueprint for future gene therapy approaches in the retina It is an exciting time in the care of patients with IRDs. and beyond. n Today, clinicians can provide treatments that can poten- tially prevent blindness for some patients with IRDs. As 1. Downing NS, Shah ND, Aminawung JA, et al. Postmarket safety events among novel therapeutics approved by the US Food and Drug Administration between 2001 and 2010. JAMA. 2017;317(18):1854-1863. these patients present to retina clinics, I hope that the 2. Russell S, Bennett J, Wellman JA, et al. Efficacy and safety of voretigene neparvovec (AAV2-hRPE65v2) in patients information presented here will be helpful and can serve as with RPE65-mediated inherited retinal dystrophy: a randomised, controlled, open-label, phase 3 trial. Lancet. n 2017;390(10097):849-860. a framework to care for these patients.

1. Duncan JL, Pierce EA, Laster AM, et al; the Foundation Fighting Blindness Scientific Advisory Board. Inherited retinal degenerations: current landscape and knowledge gaps. Transl Vis Sci Technol. 2018;7(4):6. 2. Brito-Garcia N, Del Pino-Sedeno T, Trujillo-Martin MM, et al. Effectiveness and safety of nutritional supplements in the AARON NAGIEL, MD, PhD treatment of hereditary retinal dystrophies: a systematic review. Eye (Lond). 2017;31(2):273-285. n Attending Physician, The Vision Center, Children’s Hospital Los Angeles, Los Angeles DANIEL L. CHAO, MD, PhD n Assistant Professor of Ophthalmology, Roski Eye Institute, Keck School of n Assistant Clinical Professor of Ophthalmology, Shiley Eye Institute, UC San Diego Medicine, University of Southern California, Los Angeles Health, San Diego n [email protected] n [email protected] n Financial disclosure: None n Financial disclosure: Consultant (DTx Pharma, Recens Medical, Visgenx, Zilia Health)

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