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Lancet. 2014 Mar 29;383(9923):1129-37. doi: 10.1016/S0140-6736(13)62117-0. Epub 2014 Jan 16.

Retinal gene therapy in patients with choroideremia: initial findings from a phase 1/2 clinical trial.

Author information

  • 1Nuffield Laboratory of Ophthalmology, Department of Clinical Neurosciences, University of Oxford, Oxford, UK; Oxford Eye Hospital, Oxford University Hospitals NHS Trust and NIHR Biomedical Research Centre, Oxford, UK; Moorfields Eye Hospital NHS Foundation Trust and NIHR Ophthalmology Biomedical Research Centre, London, UK. Electronic address: enquiries@eye.ox.ac.uk.
  • 2Nuffield Laboratory of Ophthalmology, Department of Clinical Neurosciences, University of Oxford, Oxford, UK; Oxford Eye Hospital, Oxford University Hospitals NHS Trust and NIHR Biomedical Research Centre, Oxford, UK; Moorfields Eye Hospital NHS Foundation Trust and NIHR Ophthalmology Biomedical Research Centre, London, UK.
  • 3Nuffield Laboratory of Ophthalmology, Department of Clinical Neurosciences, University of Oxford, Oxford, UK.
  • 4Oxford Eye Hospital, Oxford University Hospitals NHS Trust and NIHR Biomedical Research Centre, Oxford, UK.
  • 5Molecular Medicine Section, National Heart and Lung Institute, Imperial College London, London, UK.
  • 6Department of Oncology, University of Oxford, Oxford, UK.
  • 7Research Institute at the Nationwide Children's Hospital, Columbus, OH, USA.
  • 8College of Medicine, Ohio State University Medical Center, Columbus, OH, USA.
  • 9Department of Human Genetics and Nijmegen Center for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands.
  • 10Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Sciences Centre, St Mary's Hospital, Manchester, UK.
  • 11Clinical Neurosciences Group, Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.
  • 12Nuffield Laboratory of Ophthalmology, Department of Clinical Neurosciences, University of Oxford, Oxford, UK; Oxford Eye Hospital, Oxford University Hospitals NHS Trust and NIHR Biomedical Research Centre, Oxford, UK.
  • 13Moorfields Eye Hospital NHS Foundation Trust and NIHR Ophthalmology Biomedical Research Centre, London, UK; UCL Institute of Ophthalmology, London, UK.
  • 14Molecular Medicine Section, National Heart and Lung Institute, Imperial College London, London, UK; Chronic Diseases Research Centre, Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisbon, Portugal.

Abstract

BACKGROUND:

Choroideremia is an X-linked recessive disease that leads to blindness due to mutations in the CHM gene, which encodes the Rab escort protein 1 (REP1). We assessed the effects of retinal gene therapy with an adeno-associated viral (AAV) vector encoding REP1 (AAV.REP1) in patients with this disease.

METHODS:

In a multicentre clinical trial, six male patients (aged 35-63 years) with choroideremia were administered AAV.REP1 (0·6-1·0×10(10) genome particles, subfoveal injection). Visual function tests included best corrected visual acuity, microperimetry, and retinal sensitivity tests for comparison of baseline values with 6 months after surgery. This study is registered with ClinicalTrials.gov, number NCT01461213.

FINDINGS:

Despite undergoing retinal detachment, which normally reduces vision, two patients with advanced choroideremia who had low baseline best corrected visual acuity gained 21 letters and 11 letters (more than two and four lines of vision). Four other patients with near normal best corrected visual acuity at baseline recovered to within one to three letters. Mean gain in visual acuity overall was 3·8 letters (SE 4·1). Maximal sensitivity measured with dark-adapted microperimetry increased in the treated eyes from 23·0 dB (SE 1·1) at baseline to 25·3 dB (1·3) after treatment (increase 2·3 dB [95% CI 0·8-3·8]). In all patients, over the 6 months, the increase in retinal sensitivity in the treated eyes (mean 1·7 [SE 1·0]) was correlated with the vector dose administered per mm(2) of surviving retina (r=0·82, p=0·04). By contrast, small non-significant reductions (p>0·05) were noted in the control eyes in both maximal sensitivity (-0·8 dB [1·5]) and mean sensitivity (-1·6 dB [0·9]). One patient in whom the vector was not administered to the fovea re-established variable eccentric fixation that included the ectopic island of surviving retinal pigment epithelium that had been exposed to vector.

INTERPRETATION:

The initial results of this retinal gene therapy trial are consistent with improved rod and cone function that overcome any negative effects of retinal detachment. These findings lend support to further assessment of gene therapy in the treatment of choroideremia and other diseases, such as age-related macular degeneration, for which intervention should ideally be applied before the onset of retinal thinning.

FUNDING:

UK Department of Health and Wellcome Trust.

Copyright © 2014 Elsevier Ltd. All rights reserved.

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PMID:
24439297
[PubMed - indexed for MEDLINE]
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