Challenges to Gene Editing Approaches in the Retina

Mario Bonillo; Julia Pfromm; M. Dominik Fischer

doi:10.1055/a-1757-9810

Klinische Monatsblätter für Augenheilkunde, Inhaltsverzeichnis

Klin Monbl Augenheilkd 2022; 239(03): 275-283
DOI: 10.1055/a-1757-9810

Übersicht

Challenges to Gene Editing Approaches in the Retina

Herausforderungen für Gene-Editing-Ansätze in der Netzhaut

Mario Bonillo

¹Clinic of Ophthalmology, University Eye Hospital, University Hospital Tübingen, Tübingen, Germany

²Clinic of Ophthalmology, Institute for Ophthalmic Research, University Hospital Tübingen, Tübingen, Germany

,

Julia Pfromm

¹Clinic of Ophthalmology, University Eye Hospital, University Hospital Tübingen, Tübingen, Germany

²Clinic of Ophthalmology, Institute for Ophthalmic Research, University Hospital Tübingen, Tübingen, Germany

,

M. Dominik Fischer

¹Clinic of Ophthalmology, University Eye Hospital, University Hospital Tübingen, Tübingen, Germany

²Clinic of Ophthalmology, Institute for Ophthalmic Research, University Hospital Tübingen, Tübingen, Germany

³Oxford University NHS Foundation Trust, Oxford Eye Hospital, Oxford, United Kingdom of Great Britain and Northern Ireland

⁴Department of Clinical Neurosciences, University of Oxford Nuffield Laboratory of Ophthalmology, Oxford, United Kingdom of Great Britain and Northern Ireland

› Institutsangaben

Abstract

Retinal gene therapy has recently been at the cutting edge of clinical development in the diverse field of genetic therapies. The retina is an attractive target for genetic therapies such as gene editing due to the distinctive anatomical and immunological features of the eye, known as immune privilege, so that inherited retinal diseases (IRDs) have been studied in several clinical studies. Thus, rapid strides are being made toward developing targeted treatments for IRDs. Gene editing in the retina faces a group of heterogenous challenges, including editing efficiencies, off-target effects, the anatomy of the target organ, immune responses, inactivation, and identifying optimal application methods. As clustered regularly interspaced palindromic repeats (CRISPR)/CRISPR-associated nuclease (Cas) based technologies are at the forefront of current gene editing advances, their specific editing efficiency challenges and potential off-target effects were assessed. The immune privilege of the eye reduces the likelihood of systemic immune responses following retinal gene therapy, but possible immune responses must not be discounted. Immune responses to gene editing in the retina may be humoral or cell mediated, with immunologically active cells, including microglia, implicated in facilitating possible immune responses to gene editing. Immunogenicity of gene therapeutics may also lead to the inactivation of edited cells, reducing potential therapeutic benefits. This review outlines the broad spectrum of potential challenges currently facing retinal gene editing, with the goal of facilitating further advances in the safety and efficacy of gene editing therapies.

Zusammenfassung

Im vielfältigen Gebiet der Gentherapien steht die retinale Gentherapie in der vordersten Reihe der klinischen Entwicklung und findet zunehmend Anwendung im klinischen Alltag. Die Netzhaut ist aufgrund der einzigartigen anatomischen und immunologischen Eigenschaften des Auges, bezeichnet als Immunprivileg, ein attraktives Anwendungsgebiet für Gentherapien, wie etwa Geneditierung. Daher werden insbesondere die hereditären Netzhauterkrankungen (engl: Inherited retinal Dystrophies [IRDs]) in mehreren klinischen Studien untersucht. Folglich wurden rasche Fortschritte bei der Entwicklung zielgerichteter Therapien für IRDs gemacht. Dennoch steht die retinale Geneditierung zahlreichen heterogenen Herausforderungen, wie etwa deren Effizienz, Off-Target-Effekten, der Anatomie des Zielorgans, Immunreaktionen, der Inaktivierung und Ermittlung optimaler Anwendungsmethoden, gegenüber. Da Gentherapien basierend auf der CRISPR/Cas-Technologie (Clustered regular interspaced palindromic Repeats/CRISPR-assoziierte Nuklease) zunehmend an Bedeutung gewinnen, wurden ihre spezifischen Herausforderungen in Bezug auf die Editing-Effizienz und mögliche Off-Target-Effekte beurteilt. Das Immunprivileg des Auges verringert die Wahrscheinlichkeit systemischer Immunreaktionen nach einer retinalen Gentherapie, dennoch dürfen mögliche Immunreaktionen nicht außer Acht gelassen werden. Diese Immunreaktionen, induziert durch Geneditierung, können humoraler sowie zellvermittelter Natur sein, wobei immunologisch aktive Zellen wie Mikroglia mögliche Immunreaktionen auf die Geneditierung begünstigen können. Eine Immunogenität der Gentherapeutika kann auch zur Inaktivierung der editierten Zellen führen, was eine Reduzierung des therapeutischen Nutzens zur Folge hätte. Dieses Review evaluiert das breite Spektrum der Herausforderungen, denen die Geneditierung retinaler Zellen derzeit gegenübersteht, mit dem Ziel, weitere Fortschritte bei der Sicherheit und Wirksamkeit von Therapien mit Geneditierung zu ermöglichen.

Key words

retina - genetics - molecular biology

Schlüsselwörter

Netzhaut - Genetik - Molekularbiologie

Volltext

Referenzen

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