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


RESULTS
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.


CONCLUSIONS
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.


BACKGROUND
UK Department of Health and Wellcome Trust.
Nuffield 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.
Robert E
RE
MacLaren
Nuffield 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.
Markus
M
Groppe
Nuffield Laboratory of Ophthalmology, Department of Clinical Neurosciences, University of Oxford, Oxford, UK.
Alun R
AR
Barnard
Oxford Eye Hospital, Oxford University Hospitals NHS Trust and NIHR Biomedical Research Centre, Oxford, UK.
Charles L
CL
Cottriall
Molecular Medicine Section, National Heart and Lung Institute, Imperial College London, London, UK.
Tanya
T
Tolmachova
Department of Oncology, University of Oxford, Oxford, UK.
Len
L
Seymour
Research Institute at the Nationwide Children's Hospital, Columbus, OH, USA.
K Reed
KR
Clark
College of Medicine, Ohio State University Medical Center, Columbus, OH, USA.
Matthew J
MJ
During
Department of Human Genetics and Nijmegen Center for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands.
Frans P M
FP
Cremers
Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Sciences Centre, St Mary's Hospital, Manchester, UK.
Graeme C M
GC
Black
Clinical Neurosciences Group, Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.
Andrew J
AJ
Lotery
Nuffield 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.
Susan M
SM
Downes
Moorfields Eye Hospital NHS Foundation Trust and NIHR Ophthalmology Biomedical Research Centre, London, UK; UCL Institute of Ophthalmology, London, UK.
Andrew R
AR
Webster
Molecular 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.
Miguel C
MC
Seabra
D048868:Adaptor Proteins, Signal Transducing / Q000008:administration & dosage* / Q000235:genetics; D000256:Adenoviridae / Q000235:genetics; D000328:Adult; D000368:Aged; D015794:Choroideremia / Q000503:physiopathology / Q000628:therapy*; D005453:Fluorescence; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage*; D006801:Humans; D056965:Injections, Intraocular; D008297:Male; D008875:Middle Aged; D012163:Retinal Detachment / Q000503:physiopathology / Q000628:therapy; D019076:Transgenes / Q000235:genetics; D014792:Visual Acuity / Q000502:physiology
D048868:Adaptor Proteins, Signal Transducing; C081787:CHM protein, human