Gene Therapy for Inherited Retinal Disorders: Update on Clinical Trials

Abstract

Within the last decade, continuous advances in molecular biological techniques have made it possible to develop causative therapies for inherited retinal disorders (IRDs). Some of the most promising options are gene-specific approaches using adeno-associated virus-based vectors to express a healthy copy of the disease-causing gene in affected cells of a patient. This concept of gene supplementation therapy is already advocated for the treatment of retinal dystrophy in RPE65-linked Leberʼs congenital amaurosis (LCA) patients. While the concept of gene supplementation therapy can be applied to treat autosomal recessive and X-linked forms of IRD, it is not sufficient for autosomal dominant IRDs, where the pathogenic gene product needs to be removed. Therefore, for autosomal dominant IRDs, alternative approaches that utilize CRISPR/Cas9 or antisense oligonucleotides to edit or deplete the mutant allele or gene product are needed. In recent years, research retinal gene therapy has intensified and promising approaches for various forms of IRD are currently in preclinical and clinical development. This review article provides an overview of current clinical trials for the treatment of IRDs.

Zusammenfassung

Stetige Fortschritte in molekularbiologischen und genetischen Techniken ermöglichten es innerhalb der letzten Jahre, die Entwicklung ursächlicher Therapien für erbliche Netzhauterkrankungen (IRD) voranzubringen. Zu den vielversprechendsten Ansätzen gehört die Gensupplementierungstherapie, bei der mittels Adeno-assoziierten Viren (AAV) eine gesunde Kopie des krankheitsverursachenden Gens in die betroffenen Zellen eines Patienten eingeschleust wird. Dieses Therapiekonzept ist bereits bei RPE65-assoziierten Netzhautdystrophien, wie beispielsweise einer Form der Leberʼschen kongenitalen Amaurose (LCA2) als Therapie zugelassen. Während das Konzept der Gensupplementierungstherapie zur Behandlung autosomal-rezessiver und X-chromosomaler Formen von IRD angewendet werden kann, muss bei autosomal-dominanten IRDs, zusätzlich zur Gensupplementation, das pathogene Genprodukt entfernt werden. Daher sind für autosomal-dominante IRDs alternative Ansätze erforderlich, die CRISPR/Cas9- oder Antisense-Oligonukleotide verwenden, um das mutierte Allel oder Genprodukt gezielt zu eliminieren. In den letzten Jahren wurden die Forschungsaktivitäten auf dem Gebiet der retinalen Gentherapie intensiviert und etliche, vielversprechende Ansätze für verschiedene Formen der IRD befinden sich derzeit in der präklinischen und klinischen Entwicklung. Mit diesem Übersichtsartikel möchten wir einen Überblick über aktuelle Studien zur Behandlung von IRDs bieten und einen Ausblick auf zukünftige Entwicklungen geben.

Key words

AAV - adeno-associated virus - achromatopsia - inherited retinal dystrophies - Leberʼs congenital amaurosis - retinitis pigmentosa

Schlüsselwörter

AAV - Adeno-assoziierte Viren - Achromatopsie - erbliche Netzhauterkrankungen - Retinitis pigmentosa - Leberʼsche kongenitale Amaurose

Publication History

Received: 28 October 2020

Accepted: 03 February 2021

Article published online:
30 March 2021

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