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. 2018 Feb 27;6(3):167-177.
doi: 10.1080/21678707.2018.1444476.

Gene therapy for the treatment of X-linked retinitis pigmentosa

Cristina Martinez-Fernandez De La Camara  1 , Anika Nanda  1   2 , Anna Paola Salvetti  1   3 , M Dominik Fischer  1   4 , Robert E MacLaren  1   2
Affiliations

Gene therapy for the treatment of X-linked retinitis pigmentosa

Cristina Martinez-Fernandez De La Camara et al. Expert Opin Orphan Drugs. .

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).

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Conflict of interest statement

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.

Figures

Figure 1
Figure 1
OPTOS image of a male RPGR patient showing the typical peripheral ‘bone spicule’ like pigmentary changes and signs of foveal atrophy. The inner retinal vessels are also attenuated due to the loss of outer retinal cells (photo-receptors) through physiological autoregulation of blood supply – this is not believed to be pathogenic.
Figure 2
Figure 2
X-linked female carrier AF image showing the tapetal-like reflex centred on the fovea and patchy peripheral pigmentation. The mosaic picture is due to random X-inactivation generating clones of normal or degenerate photoreceptors. Since as with males, the degeneration takes time to manifest, a clearer X-linked carrier phenotype will generally be seen on the mothers of affected men rather than their daughters.
Figure 3
Figure 3
Schematic representation of the RPGR gene structure and the main alternatively spliced transcripts. Note that there is normally a splice donor site within the 5′ region of ORF15. In gene therapy, the cDNA encoding the gene is transcribed as a primary RNA transcript in the nucleus and may be subject to splicing. Hence disabling this splice donor site is also an essential part of codon optimisation.
Figure 4
Figure 4
Major RPGR protein isoforms (constitutive RPGREXON1-19 and RPGRORF15) schematic representation. RLD: RCC1-like domain, BD: basic domain.
See this image and copyright information in PMC

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