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      Clinical applications of retinal gene therapies

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          Abstract

          Retinal degenerative diseases are a major cause of blindness. Retinal gene therapy is a trail-blazer in the human gene therapy field, leading to the first FDA approved gene therapy product for a human genetic disease. The application of Clustered Regularly Interspaced Short Palindromic Repeat/Cas9 (CRISPR/Cas9)-mediated gene editing technology is transforming the delivery of gene therapy. We review the history, present, and future prospects of retinal gene therapy.

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          Efficacy and safety of voretigene neparvovec (AAV2-hRPE65v2) in patients with RPE65 -mediated inherited retinal dystrophy: a randomised, controlled, open-label, phase 3 trial

          Stephen Russell, Jean Bennett, Jennifer Wellman … (2017)
          Background Phase 1 studies have shown potential benefit of gene replacement in RPE65 -mediated inherited retinal dystrophy. This phase 3 study assessed the efficacy and safety of voretigene neparvovec in participants whose inherited retinal dystrophy would otherwise progress to complete blindness. Methods In this open-label, randomised, controlled phase 3 trial done at two sites in the USA, individuals aged 3 years or older with, in each eye, best corrected visual acuity of 20/60 or worse, or visual field less than 20 degrees in any meridian, or both, with confirmed genetic diagnosis of biallelic RPE65 mutations, sufficient viable retina, and ability to perform standardised multi-luminance mobility testing (MLMT) within the luminance range evaluated, were eligible. Participants were randomly assigned (2:1) to intervention or control using a permuted block design, stratified by age (<10 years and ≥10 years) and baseline mobility testing passing level (pass at ≥125 lux vs <125 lux). Graders assessing primary outcome were masked to treatment group. Intervention was bilateral, subretinal injection of 1·5×10 11 vector genomes of voretigene neparvovec in 0·3 mL total volume. The primary efficacy endpoint was 1-year change in MLMT performance, measuring functional vision at specified light levels. The intention-to-treat (ITT) and modified ITT populations were included in primary and safety analyses. This trial is registered with ClinicalTrials.gov, number NCT00999609, and enrolment is complete. Findings Between Nov 15, 2012, and Nov 21, 2013, 31 individuals were enrolled and randomly assigned to intervention (n=21) or control (n=10). One participant from each group withdrew after consent, before intervention, leaving an mITT population of 20 intervention and nine control participants. At 1 year, mean bilateral MLMT change score was 1·8 (SD 1·1) light levels in the intervention group versus 0·2 (1·0) in the control group (difference of 1·6, 95% CI 0·72–2·41, p=0·0013). 13 (65%) of 20 intervention participants, but no control participants, passed MLMT at the lowest luminance level tested (1 lux), demonstrating maximum possible improvement. No product-related serious adverse events or deleterious immune responses occurred. Two intervention participants, one with a pre-existing complex seizure disorder and another who experienced oral surgery complications, had serious adverse events unrelated to study participation. Most ocular events were mild in severity. Interpretation Voretigene neparvovec gene replacement improved functional vision in RPE65 -mediated inherited retinal dystrophy previously medically untreatable. Funding Spark Therapeutics.
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            Retinitis pigmentosa.

            Dyonne Hartong, Eliot L. Berson, Thaddeus Dryja (2006)
            Hereditary degenerations of the human retina are genetically heterogeneous, with well over 100 genes implicated so far. This Seminar focuses on the subset of diseases called retinitis pigmentosa, in which patients typically lose night vision in adolescence, side vision in young adulthood, and central vision in later life because of progressive loss of rod and cone photoreceptor cells. Measures of retinal function, such as the electroretinogram, show that photoreceptor function is diminished generally many years before symptomic night blindness, visual-field scotomas, or decreased visual acuity arise. More than 45 genes for retinitis pigmentosa have been identified. These genes account for only about 60% of all patients; the remainder have defects in as yet unidentified genes. Findings of controlled trials indicate that nutritional interventions, including vitamin A palmitate and omega-3-rich fish, slow progression of disease in many patients. Imminent treatments for retinitis pigmentosa are greatly anticipated, especially for genetically defined subsets of patients, because of newly identified genes, growing knowledge of affected biochemical pathways, and development of animal models.
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              Angiostatin: a novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma.

              M O'Reilly, L Holmgren, Y Shing … (1994)
              The phenomenon of inhibition of tumor growth by tumor mass has been repeatedly studied, but without elucidation of a satisfactory mechanism. In our animal model, a primary tumor inhibits its remote metastases. After tumor removal, metastases neovascularize and grow. When the primary tumor is present, metastatic growth is suppressed by a circulating angiogenesis inhibitor. Serum and urine from tumor-bearing mice, but not from controls, specifically inhibit endothelial cell proliferation. The activity copurifies with a 38 kDa plasminogen fragment that we have sequenced and named angiostatin. A corresponding fragment of human plasminogen has similar activity. Systemic administration of angiostatin, but not intact plasminogen, potently blocks neovascularization and growth of metastases. We here show that the inhibition of metastases by a primary mouse tumor is mediated, at least in part, by angiostatin.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Precis Clin Med
                Journal ID (iso-abbrev): Precis Clin Med
                Journal ID (publisher-id): pcm
                Title: Precision Clinical Medicine
                Publisher: Oxford University Press
                ISSN (Print): 2096-5303
                ISSN (Electronic): 2516-1571
                Publication date (Print): June 2018
                Publication date (Electronic): 01 June 2018
                Publication date PMC-release: 01 June 2018
                Volume: 1
                Issue: 1
                Pages: 5-20
                Affiliations
                [1 ]Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, China
                [2 ]Shiley Eye Institute, Institute for Engineering in Medicine, Institute for Genomic Medicine, University of California, San Diego, La Jolla, California, USA
                [3 ]Shanghai Key Laboratory of Ocular Fundus Diseases, Shanghai General Hospital, Shanghai Jiaodong University, Shanghai, China
                [4 ]Molecular Medicine Research Center, West China Hospital, Sichuan University, Chengdu, China
                Author notes
                Correspondence: Xiaodong Sun, xdsun@ 123456sjtu.edu.cn ; Kang Zhang, kang.zhang@ 123456gmail.com
                Article
                Publisher ID: pby004
                DOI: 10.1093/pcmedi/pby004
                PMC ID: 8982485
                SO-VID: 23688bfc-ec5b-497e-98d2-5e20ce772ea1
                Copyright © © The Author(s) 2018. Published by Oxford University Press on behalf of West China School of Medicine & West China Hospital of Sichuan University.
                License:

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@ 123456oup.com

                History
                Date received : 22 February 2018
                Date revision received : 27 March 2018
                Date accepted : 03 April 2018
                Page count
                Pages: 16
                Categories
                Subject: Review

                Data availability:

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