Is subretinal AAV gene replacement still the only viable treatment option for choroideremia?

Autor:	Han RC; Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.; Oxford Eye Hospital, Oxford University Hospitals NHS Trust, Oxford, UK., Fry LE; Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK., Kantor A; Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK., McClements ME; Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK., Xue K; Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.; Oxford Eye Hospital, Oxford University Hospitals NHS Trust, Oxford, UK., MacLaren RE; Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.; Oxford Eye Hospital, Oxford University Hospitals NHS Trust, Oxford, UK.
Jazyk:	angličtina
Zdroj:	Expert opinion on orphan drugs [Expert Opin Orphan Drugs] 2021; Vol. 9 (1), pp. 13-24. Date of Electronic Publication: 2021 Mar 24.
DOI:	10.1080/21678707.2021.1882300
Abstrakt:	Introduction: Choroideremia is an X-linked inherited retinal degeneration resulting from mutations in the CHM gene, encoding Rab escort protein-1 (REP1), a protein regulating intracellular vesicular transport. Loss-of-function mutations in CHM lead to progressive loss of retinal pigment epithelium (RPE) with photoreceptor and choriocapillaris degeneration, leading to progressive visual field constriction and loss of visual acuity. Three hundred and fifty-four unique mutations have been reported in CHM. While gene augmentation remains an ideal therapeutic option for choroideremia, other potential future clinical strategies may exist. Areas Covered: The authors examine the pathophysiology and genetic basis of choroideremia. They summarize the status of ongoing gene therapy trials and discuss CHM mutations amenable to other therapeutic approaches including CRISPR/Cas-based DNA and RNA editing, nonsense suppression of premature termination codons, and antisense oligonucleotides for splice modification. The authors undertook a literature search in PubMed and NIH Clinical Trials in October 2020. Expert Opinion: The authors conclude that AAV-mediated gene augmentation remains the most effective approach for choroideremia. Given the heterogeneity of CHM mutations and potential risks and benefits, genome-editing approaches currently do not offer significant advantages. Nonsense suppression strategies and antisense oligonucleotides are exciting novel therapeutic options; however, their clinical viability remains to be determined. Competing Interests: Declaration of interest RE MacLaren is a consultant to Biogen and receives research funding for clinical trials involving choroideremia gene therapy. 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 discussed in this work.
Databáze:	MEDLINE
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