Gene therapy for the treatment of X-linked retinitis pigmentosa

ABSTRACT

Introduction: X-linked retinitis pigmentosa caused by mutations in the retinitis pigmentosa GTPase regulator (RPGR) gene is the most common form of recessive RP. The phenotype is characterised by its severity and rapid disease progression. Gene therapy using adeno-associated viral vectors is currently the most promising therapeutic approach. However, the construction of a stable vector encoding the full-length RPGR transcript has previously proven to be a limiting step towards gene therapy clinical trials. Recently however, a codon optimised version of RPGR has been shown to increase the stability and fidelity of the sequence, conferring a therapeutic effect in murine and canine animal models.

Areas covered: This manuscript reviews the natural history of X-linked retinitis pigmentosa and the research performed from the discovery of the causative gene, RPGR, to the preclinical testing of potential therapies that have led to the initiation of three clinical trials.

Expert opinion: X-linked retinitis pigmentosa is an amenable disease to be treated by gene therapy. Codon optimisation has overcome the challenge of designing an RPGR vector without mutations, and with a therapeutic effect in different animal models. With the RPGR gene therapy clinical trials still in the early stages, the confirmation of the safety, tolerability and potency of the therapy is still ongoing.

KEYWORDS:

• Adeno-associated virus
• codon optimisation
• gene therapy
• retinitis pigmentosa
• retinitis pigmentosa GTPase regulator (RPGR)

Article highlights

• Gene therapy is a powerful therapeutic strategy for recessive single gene retinal degenerations.

• X-linked retinitis pigmentosa (XLRP) is mainly caused by mutations in the RPGR gene. Because of its severity and its high incidence, the search for an effective treatment for this disease has drawn a great deal of interest among the scientific community in the last years.

• The development of RPGR gene therapy has meant a challenge due to the instability of RPGR^ORF15 sequence that made it difficult to produce a therapeutic vector without generating new mutations.

• Codon optimisation has been successfully used as an approach to improve sequence fidelity during the development of the vector. This approach allowed the progression towards the first gene therapy clinical trial for XLRP.

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Declaration of Interest

RE MacLaren is the academic founder and director of Nightstar Therapeutics, a gene therapy company established by the University of Oxford and originally funded by the Wellcome Trust through Syncona Partners. RE MacLaren and M. Dominik Fischer are names inventors on a patent filed on behalf of the University of Oxford, relating to the expression cassette and codon optimisation of RPGR coding sequence in general. They are also consultants to Nightstar Therapeutics. 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. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

M. Dominik Fischer and RE MacLaren have received funding from Medical Research Council (UK) MR/K003690/1. Funding has also been received from Oxford NIHR Biomedical Research Centre and Royal College of Surgeons of Edinburgh