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First Gene Therapy Fda-Approved for An s FEATURE FIRST GENE THERAPY FDA-APPROVED FOR AN INHERITED RETINAL DISEASE The approval has stimulated research into gene therapies for other IRDs. BY MEGHAN J. DEBENEDICTIS, MS, LGC, MED, AND ALEKSANDRA V. RACHITSKAYA, MD he idea of gene therapy has been for clustered regularly interspaced short Scientists and companies have discussed in the medical litera- palindromic repeats) could allow edit- spent decades perfecting the use ture since as early as the 1970s. In ing of one or several sites within the of vectors for genetic material and 1972, Friedman and Roblin pro- mammalian genome.5 identifying ways to deliver them to posed that it was theoretically The most common type of gene increase therapeutic efficacy and possibleT to introduce “good” DNA to therapy is replacement gene therapy, treatment duration. Early investiga- replace defective DNA.1 Over the years, which involves replacing a mutated tions used viruses that delivered a number of gene therapy clinical trials gene that causes disease with a genes to every cell in the body, which emerged in efforts to treat genetic dis- healthy copy of that gene. It is first triggered a massive immune response eases of inborn errors of metabolism, necessary to identify the causative that could lead to organ failure. More all with varying degrees of success. mutated gene. This technology recently designed vectors deliver The basic principle of gene therapy works best in autosomal recessive specific genes to specific cells. is to put corrective genetic material biallelic disease with loss-of-function into cells to treat genetic disease. mutations. A vector is then created TARGET: IRDS Several gene therapy approaches, to carry a wild-type copy of the With the eye’s unique immunologic including replacement gene therapy, gene into the cell of interest. The privilege, inherited retinal diseases optogenetics, addition of a growth transfected gene is not incorporated (IRDs) have become one of the lead- factor, suppression gene therapy, and into the host DNA but is expressed, ing targets in gene therapy research gene editing, have been proposed in resulting in production of a protein over the past 15 years. Successful attempts to treat various ophthalmo- with normal function. treatment and restoration of vision logic conditions. Optogenetics focuses on creating artificial photoreceptors to restore AT A GLANCE photosensitivity. This is accomplished by gene delivery of light-activated s The most common type of gene therapy is replacement gene therapy, in optogenetic tools (channels or pumps) to surviving cells, such as ganglion cells, which a mutated gene that causes disease is replaced with a healthy that remain intact in the retinal circuit copy of that gene. in various diseases.2 It has been posited that genetically added growth factor s RPE65 gene mutations account for up to 10% of autosomal recessive proteins, such as adenovirus-expressed endostatin and angiostatin gene prod- Leber congenital amaurosis and early-onset retinal dystrophy cases. ucts, could have anti-VEGF properties.3 Short-interfering RNAs could be s The positive results of gene therapy clinical trials for RPE65-mediated used for down-regulation of gene retinal dystrophy led to the first US regulatory approval of a gene expression, resulting in functional inac- tivation of the targeted genes.4 Finally, therapy in January 2018. technologies such as CRISPR (standing 36 RETINA TODAY | APRIL 2018 FEATURE s ©istockphoto 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 s FEATURE WITH THE PIVOTAL SUCCESS AND FDA APPROVAL Leber hereditary optic neuropathy, and Usher syndrome (MYO7A and USH2A). OF VORETIGENE FOR TREATMENT OF BIALLELIC Advances in the field of gene ther- apy make the accurate diagnosis of hereditary retinal dystrophies more RPE65-MEDIATED INHERITED RETINAL DISEASE, important than ever. Genetic testing is crucial to identify the underlying ONGOING RESEARCH IN OTHER INHERITED RETINAL cause of disease in this patient popu- lation and to allow potential inter- DYSTROPHIES HAS EXPLODED. vention with gene therapy and other novel therapies. The burgeoning field of gene therapy provides hope to patients who previously had no hope Eligible participants for this trial (Luxturna; Spark Therapeutics) of preserving or regaining vision. n included patients aged 3 years or older is approved for the treatment of with best corrected visual acuity of patients with confirmed biallelic 1. Friedmann T, Roblin R. Gene therapy for human genetic disease? Science. 20/60 or worse in each eye or visual RPE65 mediated IRD. It is the first 1972;175(4025):949-955. 2. Busskamp V, Picaud S, Sahel JA, Roska B. Optogenetic therapy for retinitis field of less than 20°. The primary out- directly administered gene therapy pigmentosa. Gene Ther. 2012;19(2):169-175. come of the study was multiluminance approved in the United States that 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 mobility testing (MLMT). Patients targets a genetic disease caused by growth factor expression in tumor cells. FASEB J. 2002;16(13):1802-1804. were required to follow a maze at dif- mutations in a single gene. 4. Cong L, Ran FA, Cox D, et al. Multiplex genome engineering using CRISPR/Cas systems. Science. 2013;339(6121):819-823. ferent illumination (lux) levels ranging Voretigene is administered via 5. Cong L, Ran FA, Cox D, Lin S, Barretto R, Habib N, Hsu PD, Wu X, Jiang from a brightly lit office environment subretinal injection in both eyes W, Marraffini L, Zhang F. Multiplex genome engineering using CRISPR/Cas systems. Science. 2013;3:1231143. to a moonless night. separately and on separate days. The 6. Acland GM, Aguirre GD, Ray J, et al. Gene therapy restores vision in a At 1 year, there was a statistically surgery, which is performed by a canine model of childhood blindness. Nat Genet. 2001;28(1):92-95. 7. Cai X, Conley SM, Naash MI. RPE65: role in the visual cycle, human retinal significant difference in improve- vitreoretinal surgeon, requires pars disease, and gene therapy. Ophthalmic Genet. 2009;30(2):57-62. ment in mean bilateral MLMT plana vitrectomy and subretinal 8. Russell S, Bennett J, Wellman JA,. Efficacy and safety of voretigene neparvovec (AAV2-hRPE65v2) in patients with RPE65-mediated inherited favoring the intervention group. injection of a total volume of 0.3 mL. retinal dystrophy: a randomised, controlled, open-label, phase 3 trial. Moreover, 13 (65%) of 20 interven- The recommended site of injection Lancet. 2017;390(10097):849-860. 9. Kumaran N, Moore AT, Weleber RG, Michaelides M. Leber congenital amau- tion participants, but no control is located along the superior vascular rosis/early-onset severe retinal dystrophy: clinical features, molecular genetics participants, passed MLMT at arcade, at least 2 mm distal to the and therapeutic interventions. Br J Ophthalmol. 2017;101(9):1147-1154. 10 10. Luxturna [package insert]. Spark Therapeutics. 2017. the lowest luminance level tested center of the fovea. Given the small 11. A US drugmaker offers to cure rare blindness for $850,000. CNBC (1 lux), demonstrating the maximum number of patients who qualify for website. January 3, 2018. www.cnbc.com/2018/01/03/spark-therapeutics- luxturna-gene-therapy-will-cost-about-850000.html. Accessed March possible improvement. The authors this specific gene therapy, there are a 16, 2018. reported no product-related serious few dedicated sites across the coun- adverse events or deleterious try that are offering the treatment. immune responses. Improvements The cost of treatment is currently MEGHAN J. DEBENEDICTIS, MS, LGC, MED in both navigational abilities and $425,000 per eye.11 n Licensed, Certified Genetic Counselor, Cole Eye light sensitivity were evident within Institute, Cleveland Clinic Foundation, Cleveland, Ohio the first 30 days after subretinal MORE TO COME n [email protected] delivery and remained stable for With the pivotal success and US n Financial disclosure: Consultant (Spark Therapeutics, 1 year, as they have for at least Food and Drug Administration Second Sight Medical Products) 3 years in participants in the previ- approval of voretigene for treatment ALEKSANDRA V.
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