title: Gene therapy for choroideremia using an adeno-associated viral (AAV) vector.
abstract: Choroideremia is an outer retinal degeneration with a characteristic clinical appearance that was first described in the nineteenth century. The disorder begins with reduction of night vision and gradually progresses to blindness by middle age. The appearance of the fundus in sufferers is recognizable by the characteristic pale color caused by the loss of the outer retina, retinal-pigmented epithelium, and choroidal vessels, leading to exposure of the underlying sclera. Choroideremia shows X-linked recessive inheritance and the choroideremia gene (CHM) was one of the first to be identified by positional cloning in 1990. Subsequent identification and characterization of the CHM gene, which encodes Rab escort protein 1 (REP1), has led to better comprehension of the disease and enabled advances in genetic diagnosis. Despite several decades of work to understand the exact pathogenesis, no established treatments currently exist to stop or even slow the progression of retinal degeneration in choroideremia. Encouragingly, several specific molecular and clinical features make choroideremia an ideal candidate for treatment with gene therapy. This work describes the considerations and challenges in the development of a new clinical trial using adeno-associated virus (AAV) encoding the CHM gene.
authors.affiliation: Nuffield Laboratory of Ophthalmology, Department of Clinical Neurosciences and Oxford Biomedical Research Centre, University of Oxford, The John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom.
authors.forename: Alun R
authors.initials: AR
authors.lastname: Barnard
authors.affiliation: Nuffield Laboratory of Ophthalmology, Department of Clinical Neurosciences and Oxford Biomedical Research Centre, University of Oxford, The John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom Moorfields Eye Hospital and NIHR Biomedical Research Centre for Ophthalmology, London EC1V 2PD, United Kingdom.
authors.forename: Markus
authors.initials: M
authors.lastname: Groppe
authors.affiliation: Nuffield Laboratory of Ophthalmology, Department of Clinical Neurosciences and Oxford Biomedical Research Centre, University of Oxford, The John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom Moorfields Eye Hospital and NIHR Biomedical Research Centre for Ophthalmology, London EC1V 2PD, United Kingdom.
authors.forename: Robert E
authors.initials: RE
authors.lastname: MacLaren
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000818:Animals; D015794:Choroideremia / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D017321:Clinical Trials, Phase I as Topic; D000229:Dependovirus; D004195:Disease Models, Animal; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D012160:Retina / Q000473:pathology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C081787:CHM protein, human