Emerging gene therapy products for RPGR-associated X-linked retinitis pigmentosa

ABSTRACT

Introduction

Mutations in the RPGR gene are responsible for one of the most prevalent and severe types of retinitis pigmentosa. Gene therapy has shown great promise to treat inherited retinal diseases, and currently, four RPGR gene therapy vectors are being evaluated in clinical trials.

Areas covered

This manuscript reviews the gene therapy products that are in development for X-linked retinitis pigmentosa caused by mutations in RPGR, and the challenges that scientists and clinicians have faced.

Expert opinion

The development of a gene therapy product for RPGR-associated retinal degeneration has been a great challenge due to the incomplete understanding of the underlying genetics and mechanism of action of RPGR, and on the other hand, due to the instability of the RPGR gene. Three of the four gene therapy vectors currently in clinical trials include a codon-optimized version of the human RPGR sequence, and the other vector contains a shortened version of the human RPGR. To date, the only Phase I/II results published in a peer-reviewed journal demonstrate a good safety profile and an improvement in the visual field using a codon optimized version of RPGR^ORF15.

KEYWORDS:

• Adeno-associated virus (AAV)
• gene therapy
• inherited retinal diseases
• retinitis pigmentosa
• retinitis pigmentosa GTPase regulator (RPGR)

Article highlights

• Retinitis pigmentosa caused by mutations in the RPGR gene is a severe and relatively high prevalent type of IRD. This disease has proven to be a good candidate for gene replacement therapy using AAVs, the most common vector used in ophthalmology.

• The molecular and biological complexity of RPGR represents the biggest challenge to develop a gene therapy vector and to predict the likelihood of success and long-term effect of a gene therapy treatment.

• The instability of the human RPGR^ORF15 nucleotide sequence makes difficult to produce the full-length RPGR gene without introducing spontaneous mutations that could alter or eliminate the RPGR protein function. Codon optimization can be used as a strategy to improve the stability of the sequence during the production process.

• The understanding of the pathophysiology of RPGR-associated RP is incomplete. The underlying genetics, mechanism of action and pathogenesis of RPGR require additional investigations that will contribute to the generation of more effective and targeted gene therapies.

• Different RPGR gene therapy vectors and delivery routes are currently being investigated in clinical trials to identify a safe and effective treatment for RPGR-associated X-linked RP. To date, the initial results of one of the clinical trials have been made available in a per-reviewed journal, demonstrating a good safety profile and an improvement in the visual field using a codon optimized version of RPGR^ORF15.

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Declaration of interest

RE MacLaren has previously received grant funding from Biogen and has previously provided independent consultancy advice on X-linked retinitis pigmentosa to Biogen Inc. and Janssen Pharmaceuticals. RE MacLaren is also listed as an inventor on a patent for X-linked retinitis pigmentosa gene therapy owned by the University of Oxford. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

A reviewer on this manuscript is an investigator for MeiraGTx-sponsored trials of gene therapy for RPGR. Another reviewer on this manuscript is on the Scientific Advisory Board of AGTC, one of the companies developing RPGR gene therapy. MeiraGTx reviewed and provided comments on the manuscript. The views expressed in the manuscript are those of the authors and do not reflect the views of MeiraGTx. MeiraGTx has provided a Letter to the Editor (https://doi.org/10.1080/14728214.2022.2152202). Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

Medical Research Council (UK) MR/K003690/1 award to RE MacLaren, Oxford NIHR Biomedical Research Centre, and Royal College of Surgeons of Edinburgh.