Choroideremia: molecular mechanisms and development of AAV gene therapy

ABSTRACT

Introduction: Choroideremia is an X-linked inherited retinal degeneration that causes blindness in afflicted males by middle age. The causative gene, CHM, plays a key role in intracellular trafficking pathways, and its disruption impairs cell homeostasis.

Areas covered: The mechanism by which mutations in CHM cause choroideremia is still under debate. Here we describe the molecular defects in choroideremia cells regarding both the deficiency of prenylation and the involvement of Rab GTPases. Important in vivo and in vitro studies that contributed to the current knowledge are also discussed. Finally, the rationale for the development of a treatment strategy using AAV for gene replacement is presented, together with other treatment strategies under consideration.

Expert opinion: Despite ubiquitous expression of the CHM gene, the primary defect in choroideremia is driven by retinal pigment epithelium (RPE) and photoreceptors degeneration. Here we discuss how impairment of vesicular trafficking pathways in the RPE plays a major role in the molecular pathogenesis of choroideremia. Moreover, this defect is likely restored by subretinal delivery of a functional copy of CHM using AAV, as evidenced by clinical trial results. The surgical complexity of delivering the AAV vector to the target area remains as the main challenge to this therapy.

Abbreviations: AAV: adeno-associated virus; BCD: Bietti’s crystalline dystrophy; CHM: choroideremia; CHML: choroideremia-like; Dfp: days post-fertilization; EMA: European Medicines Agency; ERG: electroretinogram; ETDRS: Early Treatment Diabetic Retinopathy Study; FDA: Food and Drug Administration; FTase: farnesyl transferase; GFP: green fluorescent protein; GGPP: geranylgeranyl-diphosphate; GGTase-I: geranylgeranyl transferase type-I; GGTase-II: geranylgeranyl transferase type-II; HMG-CoA: 3-hydroxy-3-methylglutayl-CoA; HMGCR: HMG-CoA reductase; iPSC: induced pluripotent stem cells; IRDs: inherited retinal diseases; KO: knockout; LCA: Leber congenital amaurosis; NMD: nonsense-mediated mRNA decay; OCT: optical coherence tomography; PMBCs: peripheral blood mononuclear cells; POS: photoreceptor outer segments; PTCs: premature termination codons; Rab GGTase: Rab geranylgeranyl transferase; REP: Rab escort protein; RPE: retinal pigment epithelium; TRIDs: translational read-through inducing drugs; WPRE: woodchuck post-transcriptional regulatory element

KEYWORDS:

• AAV
• choroideremia
• clinical trials
• gene therapy
• prenylation
• Rab GTPases

Article highlights

• Choroideremia is a degenerative inherited retinal disease for which there is no treatment yet.

• The product of the causative gene, REP1, has a well-described function: it regulates intracellular trafficking pathways by prenylation of Rab GTPases.

• In choroideremia, the impairment of trafficking pathways in the RPE specialised cell layer disrupts cell homeostasis and causes retinal degeneration.

• Targeting the RPE and photoreceptors of choroideremia patients using an AAV to deliver a healthy copy of CHM has shown promising results.

• The surgical complexity of delivering the AAV vector to the target area remains as the main challenge for the future of AAV gene therapy for choroideremia.

This box summarizes key points contained in the article.

Acknowledgments

The authors would like to thank all trial participants, and Dr Carolina Matos for her valuable help with figure illustration.

Declaration of interest

MI Patrício and RE MacLaren are named inventors on patents relating to choroideremia gene therapy owned by the University of Oxford and Nightstar Therapeutics, a gene therapy company established by the University of Oxford and based at the Wellcome Trust Building, 215 Euston Road, London NW1 2BE, UK. AR Barnard is a consultant for Nightstar Therapeutics. RE MacLaren is a scientific co-founder of Nightstar Therapeutics. RE MacLaren receives research funding from Nightstar Therapeutics through the University of Oxford. RE MacLaren is part of the scientific advisory board for Spark Therapeutics Inc. 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 has disclosed that they are a co-principal investigator of one of the ongoing gene therapy trials for choroideremia.

Additional information

Funding

This research was supported and funded by the National Institute for Health Research (NIHR), Oxford Biomedical Research Centre (BRC), Fight for Sight (grant no. 1718/19), the Royal College of Surgeons of Edinburgh, and by Nightstar Therapeutics. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health.