Research Institute at the Nationwide Childrens Hospital

Columbus, OH, United States

Research Institute at the Nationwide Childrens Hospital

Columbus, OH, United States
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PubMed | St. Mary's University, Ohio State University, Imperial College London, University of Southampton and 5 more.
Type: Clinical Trial, Phase I | Journal: Lancet (London, England) | Year: 2014

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.In a multicentre clinical trial, six male patients (aged 35-63 years) with choroideremia were administered AAV.REP1 (06-1010(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.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 38 letters (SE 41). Maximal sensitivity measured with dark-adapted microperimetry increased in the treated eyes from 230 dB (SE 11) at baseline to 253 dB (13) after treatment (increase 23 dB [95% CI 08-38]). In all patients, over the 6 months, the increase in retinal sensitivity in the treated eyes (mean 17 [SE 10]) was correlated with the vector dose administered per mm(2) of surviving retina (r=082, p=004). By contrast, small non-significant reductions (p>005) were noted in the control eyes in both maximal sensitivity (-08 dB [15]) and mean sensitivity (-16 dB [09]). 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.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.UK Department of Health and Wellcome Trust.


MacLaren R.E.,University of Oxford | MacLaren R.E.,Moorfi Elds Eye Hospital NHS Foundation Trust | Groppe M.,University of Oxford | Groppe M.,Moorfi Elds Eye Hospital NHS Foundation Trust | And 14 more authors.
The Lancet | Year: 2014

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 eff ects of retinal gene therapy with an adenoassociated 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 × 1010 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-rfsti of surviving retina (r=0.82, p=0.04). By contrast, small non-signifi cant 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 fi xation 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 eff ects of retinal detachment. These fi ndings 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.

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