CRISPR-Corrected RPE Monolayer Patches for Geographic Atrophy in Age-Related Macular Degeneration: A Perspective
DOI:
https://doi.org/10.63501/w407zz65Abstract
Abstract
Geographic atrophy (GA), the atrophic late-stage form of age-related macular degeneration (AMD), is a leading cause of irreversible central vision loss in older adults and lacks broadly restorative therapies. Recent advances in tissue engineering have produced polarized, scaffold-supported retinal pigment epithelium (RPE) monolayer patches that can be surgically implanted into GA lesions and show safety and early signs of anatomical and functional benefit (1,2,3). Concurrently, CRISPR-based genome editing (including base and prime editors) has matured to the point where disease-associated alleles and maladaptive pathways implicated in AMD (complement dysregulation, oxidative stress, lipid processing, ARMS2/HTRA1 locus effects) can be corrected or modulated in patient-derived induced pluripotent stem cells (iPSCs) with increasing precision (8,9,10). Integrating CRISPR correction into an autologous iPSC-RPE patch strategy promises a dual-action therapy: (a) structural replacement of lost RPE and restoration of a polarized monolayer niche and (b) reduction of cell-intrinsic susceptibility to AMD pathology by editing high-impact alleles or tuning pathogenic pathways. This Perspective outlines the biological rationale, a pragmatic GMP-compatible manufacturing and QC pipeline, preclinical evaluation milestones, clinical endpoints, key technical and regulatory challenges, and proposed mitigations to accelerate safe translation of CRISPR-corrected RPE monolayer patches from bench to first-in-human studies.
References
References
1) da Cruz L, Fynes K, Georgiadis O, Kerby J, Luo YH, Ahmado A, Vernon A, Daniels JT, Nommiste B, Hasan SM, Gooljar SB. Phase 1 clinical study of an embryonic stem cell–derived retinal pigment epithelium patch in age-related macular degeneration. Nature biotechnology. 2018 Apr;36(4):328-37.
2) Mandai M, Watanabe A, Kurimoto Y, Hirami Y, Morinaga C, Daimon T, Fujihara M, Akimaru H, Sakai N, Shibata Y, Terada M. Autologous induced stem-cell–derived retinal cells for macular degeneration. New England Journal of Medicine. 2017 Mar 16;376(11):1038-46.
3) Sharma R, Khristov V, Rising A, Jha BS, Dejene R, Hotaling N, Li Y, Stoddard J, Stankewicz C, Wan Q, Zhang C. Clinical-grade stem cell–derived retinal pigment epithelium patch rescues retinal degeneration in rodents and pigs. Science translational medicine. 2019 Jan 16;11(475):eaat5580.
4) Kamao H, Mandai M, Ohashi W, Hirami Y, Kurimoto Y, Kiryu J, Takahashi M. Evaluation of the surgical device and procedure for extracellular matrix–scaffold–supported human iPSC–derived retinal pigment epithelium cell sheet transplantation. Investigative ophthalmology & visual science. 2017 Jan 1;58(1):211-20.
5) Mehat MS, Sundaram V, Ripamonti C, Robson AG, Smith AJ, Borooah S, Robinson M, Rosenthal AN, Innes W, Weleber RG, Lee RW. Transplantation of human embryonic stem cell-derived retinal pigment epithelial cells in macular degeneration. Ophthalmology. 2018 Nov 1;125(11):1765-75.
6) Bakondi B, Lv W, Lu B, Jones MK, Tsai Y, Kim KJ, Levy R, Akhtar AA, Breunig JJ, Svendsen CN, Wang S. In vivo CRISPR/Cas9 gene editing corrects retinal dystrophy in the S334ter-3 rat model of autosomal dominant retinitis pigmentosa. Molecular Therapy. 2016 Mar 1;24(3):556-63.
7) Maeder ML, Stefanidakis M, Wilson CJ, Baral R, Barrera LA, Bounoutas GS, Bumcrot D, Chao H, Ciulla DM, DaSilva JA, Dass A. Development of a gene-editing approach to restore vision loss in Leber congenital amaurosis type 10. Nature medicine. 2019 Feb;25(2):229-33.
8) Tsai SQ, Zheng Z, Nguyen NT, Liebers M, Topkar VV, Thapar V, Wyvekens N, Khayter C, Iafrate AJ, Le LP, Aryee MJ. GUIDE-seq enables genome-wide profiling of off-target cleavage by CRISPR-Cas nucleases. Nature biotechnology. 2015 Feb;33(2):187-97.
9) Hsu PD, Lander ES, Zhang F. Development and applications of CRISPR-Cas9 for genome engineering. Cell. 2014 Jun 5;157(6):1262-78.
10) Kosicki M, Tomberg K, Bradley A. Repair of double-strand breaks induced by CRISPR–Cas9 leads to large deletions and complex rearrangements. Nature biotechnology. 2018 Sep;36(8):765-71.
Downloads
Published
Issue
Section
License
This article is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0), which permits use, sharing, adaptation, distribution, and reproduction in any medium or format, provided appropriate credit is given to the author(s) and the source. To view a copy of this license, visit: https://creativecommons.org/licenses/by/4.0