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RPE65 s With the eye’s unique immunologic unique eye’s the With Scientists and companies have companies and Scientists identifying ways to deliver them to them deliver to ways identifying and efficacy therapeutic increase investiga Early duration. treatment delivered that viruses used tions which body, the in cell every to genes response immune massive a triggered More failure. organ to lead could that deliver vectors designed recently cells. specific to genes specific TARGET: IRD diseases retinal inherited privilege, lead the of one become have (IRDs) research therapy gene in targets ing Successful years. 15 past the over vision of restoration and treatment spent decades perfecting the use the perfecting decades spent and material genetic for vectors of - ALEKSANDRA V. RACHITSKAYA, MD MD ALEKSANDRA V. RACHITSKAYA, and , d 5 ) could allow edit allow could ) gene mutations account for up to 10% of autosomal recessive 10% of autosomal recessive to for up mutations account gene AT A GLANCE The positive results of clinical trials for therapy clinical trials The positive results of gene The most common type of gene therapy is replacement gene therapy, in gene therapy, in therapy is replacement of gene common type The most retinal dystrophy led to the first US regulatory approval of a gene gene regulatory approval of a the first US led to retinal dystrophy therapy in January 2018. RPE65 Leber congenital amaurosis and early-onset retinal dystrophy cases. which a mutated gene that causes disease is replaced with a healthy disease is replaced with a healthy which a mutated gene that causes copy of that gene.    clustered regularly interspaced short interspaced regularly clustered

The most common type of gene of type common most The s s s mutated gene. This technology technology This gene. mutated recessive autosomal in best works loss-of-function with disease biallelic created then is vector A mutations. the of copy wild-type a carry to The interest. of cell the into gene incorporated not is gene transfected expressed, is but DNA host the into protein a of production in resulting function. normal with for repeats palindromic the within sites several or one of ing genome. mammalian therapy, gene replacement is therapy mutated a replacing involves which a with disease causes that gene first is It gene. that of copy healthy causative the identify to necessary

3 ------The approval has stimulated research into gene therapies for other IRDs. therapies gene into research stimulated approval has The MS, LGC, ME BY MEGHAN J. DEBENEDICTIS, Finally, 4 Over the years,the Over 1 It has been positedbeen has It 2

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he idea of gene therapy has beenhas therapy gene of idea he litera medical the in discussed In1970s. the as early as since ture pro Roblin and Friedman 1972, theoreticallywas it that posed Optogenetics focuses on creatingon focuses Optogenetics

The basic principle of gene therapygene of principle basic The T ucts, could have anti-VEGF properties. anti-VEGF have could ucts, becould RNAs Short-interfering gene of down-regulation for used inac functional in resulting expression, genes. targeted the of tivation (standingCRISPR as such technologies to surviving cells, such as ganglion cells,ganglion as such cells, surviving to circuitretinal the in intact remain that diseases. various in factor growth added genetically that adenovirus-expressedas such proteins, prod gene angiostatin and endostatin attempts to treat various ophthalmo various treat to attempts conditions. logic restoreto photoreceptors artificial accomplishedis This photosensitivity. light-activatedof delivery gene by pumps)or (channels tools optogenetic into cells to treat genetic disease.genetic treat to cells into approaches, therapy gene Several therapy,gene replacement including growtha of addition optogenetics, andtherapy, gene suppression factor, inproposed been have editing, gene a number of gene therapy clinical trialsclinical therapy gene of number a dis genetic treat to efforts in emerged metabolism,of errors inborn of eases success. of degrees varying with all materialgenetic corrective put to is possible to introduce “good” DNA toDNA “good” introduce to possible DNA. defective replace

FOR AN INHERITED RETINAL DISEASE RETINAL INHERITED AN FOR FIRST GENE THERAPY FDA-APPROVED FDA-APPROVED THERAPY GENE FIRST TODAY

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in vivo was first achieved in canine regeneration in photoreceptor cells.7 with this condition have an early-onset models with RPE65-related retinal However, despite the inability of retinal dystrophy phenotype with degeneration.6 The successful delivery the RPE cells to provide sufficient profound night blindness from birth of a wild-type RPE65 gene using a 11-cis retinal to the photoreceptors but residual cone-mediated vision and recombinant adeno-associated virus in RPE65-related retinal degeneration, often mild, if any, nystagmus. The dis- (AAV), with positive results, paved the photoreceptors degenerate ease usually manifests in childhood. the way for human clinical trials. slowly, so that phenotypic recovery In healthy eyes, RPE65 is expressed is possible through restoration of CLINICAL TRIAL RESULTS in the retinal pigment epithelium the missing enzyme to the RPE.8 Initially restricted to adults and (RPE) and encodes an RPE-specific RPE65-mediated retinal dystrophy is involving treatment of only one eye, 65 kD protein, all-trans retinyl ester an autosomal recessive disease that RPE65 gene therapy trials have since isomerase, an enzyme crucial to the occurs due to biallelic loss-of-function expanded to include children and retinoid cycle. The enzyme plays an mutations in the RPE65 gene, making bilateral treatment. The results of a essential role in the visual cycle. RPE65 it an attractive condition for gene phase 3 RPE65 gene therapy clinical is responsible for the conversion of replacement therapy.7 trial, published last year, showed all-trans retinyl esters to 11-cis reti- RPE65 gene mutations account for improvement in functional vision in nol during phototransduction. The up to 10% of autosomal recessive treated patients, in comparison with 11-cis retinol is converted to 11-cis Leber congenital amaurosis and early- untreated control participants, at retinal and is used in visual pigment onset retinal dystrophy cases.9 Patients 1 year.8

APRIL 2018 | RETINA TODAY 37 - . - - - n Science and and d . 2002;16(13):1802-1804. . 2001;28(1):92-95. MYO7A . 2009;30(2):57-62. . 2017;101(9):1147-1154. FASEB J Nat Genet Br J Ophthalmol . 2013;339(6121):819-823. Ophthalmic Genet . 2012;19(2):169-175. Science . 2013;3:1231143. ). Gene Ther Science . 2017;390(10097):849-860. Advances in the field of gene ther gene of field the in Advances Vitreoretinal Physician, Cole Eye Institute, Cleveland Vitreoretinal Physician, Cole Eye Institute, Cleveland [email protected] Financial disclosure: None Licensed, Certified Genetic Counselor, Cole Eye Licensed, Certified Genetic Counselor, Cole Eye [email protected] Financial disclosure: Consultant (Spark Therapeutics, Clinic Foundation, and Assistant Professor of Clinic Foundation, and Assistant Professor of Ophthalmology, Cleveland Clinic Lerner College of Medicine; both in Cleveland, Ohio Institute, Cleveland Clinic Foundation, Cleveland, Ohio Second Sight Medical Products)     Leber hereditary optic neuropathy, neuropathy, optic hereditary Leber ( syndrome Usher and USH2A of diagnosis accurate the make apy more dystrophies retinal hereditary testing Genetic ever. than important underlying the identify to crucial is popu patient this in disease of cause inter potential allow to and lation other and therapy gene with vention field burgeoning The therapies. novel to hope provides therapy gene of hope no had previously who patients vision. regaining or preserving of 1. Friedmann T, Roblin R. Gene therapy for human genetic disease? n n n pigmentosa. 3. Hajitou A, Grignet C, Devy L, et al. The antitumoral effect of endostatin and angiostatin is associated with a down-regulation of vascular endothelial growth factor expression in tumor cells. 4. Cong L, Ran FA, Cox D, et al. Multiplex genome engineering using CRISPR/Cas systems. 5. Cong L, Ran FA, Cox D, Lin S, Barretto R, Habib N, Hsu PD, Wu X, Jiang W, Marraffini L, Zhang F. Multiplex genome engineering using CRISPR/Cas systems. 6. Acland GM, Aguirre GD, Ray J, et al. Gene therapy restores vision in a canine model of childhood blindness. 7. Cai X, Conley SM, Naash MI. RPE65: role in the visual cycle, human retinal disease, and gene therapy. 8. Russell S, Bennett J, Wellman JA,. Efficacy and safety of (AAV2-hRPE65v2) in patients with RPE65-mediated inherited retinal dystrophy: a randomised, controlled, open-label, phase 3 trial. Lancet 9. Kumaran N, Moore AT, Weleber RG, Michaelides M. Leber congenital amau rosis/early-onset severe retinal dystrophy: clinical features, molecular genetics and therapeutic interventions. 10. Luxturna [package insert]. . 2017. 11. A US drugmaker offers to cure rare blindness for $850,000. CNBC website. January 3, 2018. www.cnbc.com/2018/01/03/spark-therapeutics- luxturna-gene-therapy-will-cost-about-850000.html. Accessed March 16, 2018. MEGHAN J. DEBENEDICTIS, MS, LGC, ME n n n ALEKSANDRA V. RACHITSKAYA, MD 1972;175(4025):949-955. 2. Busskamp V, Picaud S, Sahel JA, Roska B. Optogenetic therapy for retinitis ), - ), CNGA3 PDE6B and , and , Given the small small the Given 10 11 -mediated IRD, IRD, -mediated CNGB3 PDE6A , RPE65 RLBP1 , mediated IRD. It is the first first the is It IRD. mediated With the pivotal success and US US and success pivotal the With Voretigene is administered via via administered is Voretigene RPGR gyrate atrophy, pigmentosa retinitis atrophy, gyrate ( $425,000 per eye. per $425,000 MORE TO COME Administration Drug and Food treatment for voretigene of approval biallelic of has IRDs other in research ongoing is research therapy Gene exploded. stages various at conducted being juvenile X-linked choroideremia, for disease, Stargardt retinoschisis, achromatopsia( surgery, which is performed by a a by performed is which surgery, pars requires surgeon, vitreoretinal subretinal and vitrectomy plana mL. 0.3 of volume total a of injection injection of site recommended The vascular superior the along located is the to distal mm 2 least at arcade, fovea. the of center for qualify who patients of number a are there therapy, gene specific this coun the across sites dedicated few treatment. the offering are that try currently is treatment of cost The (Luxturna; Spark Therapeutics) Therapeutics) Spark (Luxturna; of treatment the for approved is biallelic confirmed with patients RPE65 therapy gene administered directly that States United the in approved by caused disease genetic a targets gene. single a in mutations eyes both in injection subretinal The days. separate on and separately - - -

- - gene gene RPE65 8 -MEDIATED INHERITED RETINAL DISEASE, RETINAL DISEASE, -MEDIATED INHERITED APRIL 2018

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lux), demonstrating the maximum maximum the demonstrating lux), This groundbreaking work and and work groundbreaking This At 1 year, there was a statistically statistically a was there year, 1 At Eligible participants for this trialthis for participants Eligible year, as they have for at least least at for have they as year, previ the in participants in years RPE65 the results of these of results the regulatory to led trials therapy US the by therapy this of approval in Administration Drug and Food neparvovec-rzyl Voretigene January. delivery and remained stable for for stable remained and delivery 1 3 trial. 1 phase ous REGULATORY APPROVAL possible improvement. The authors authors The improvement. possible serious product-related no reported deleterious or events adverse Improvements responses. immune and abilities navigational both in within evident were sensitivity light subretinal after days 30 firstthe favoring the intervention group. group. intervention the favoring interven 20 of (65%) 13 Moreover, control no but participants, tion at MLMT passed participants, tested level luminance lowest the (1 ferent illumination (lux) levels ranginglevels (lux) illumination ferent environmentoffice lit brightly a from night. moonless a to improve in difference significant MLMT bilateral mean in ment included patients aged 3 years or olderor years 3 aged patients included ofacuity visual corrected best with visualor eye each in worse or 20/60 out primary The 20°. than less of field multiluminancewas study the of come Patients (MLMT). testing mobility dif at maze a follow to required were DYSTROPHIES HAS EXPLODED. DYSTROPHIES OF VORETIGENE FOR TREATMENT OF BIALLELIC FOR TREATMENT OF BIALLELIC OF VORETIGENE RETINAL IN OTHER INHERITED ONGOING RESEARCH WITH THE PIVOTAL SUCCESS AND FDA APPROVAL FDA APPROVAL SUCCESS AND THE PIVOTAL WITH RETINA TODAY

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