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

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

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
0140-6736
1129-1137
McLaren, R.E.
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Groppe, M.
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Barnard, A.R.
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Cottriall, C.L.
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Tolmachova, T.
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Seymour, L.
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Clark, K.R.
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During, M.J.
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Cremers, F.P.
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Black, G.C.
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Lotery, A.J.
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Downes, S.M.
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Webster, A.R.
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Seabra, M.C.
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McLaren, R.E.
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Groppe, M.
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Barnard, A.R.
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Cottriall, C.L.
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Tolmachova, T.
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Seymour, L.
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Clark, K.R.
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During, M.J.
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Cremers, F.P.
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Black, G.C.
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Lotery, A.J.
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Downes, S.M.
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Webster, A.R.
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Seabra, M.C.
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McLaren, R.E., Groppe, M., Barnard, A.R., Cottriall, C.L., Tolmachova, T., Seymour, L., Clark, K.R., During, M.J., Cremers, F.P., Black, G.C., Lotery, A.J., Downes, S.M., Webster, A.R. and Seabra, M.C. (2014) Retinal gene therapy in patients with choroideremia: initial findings from a phase 1/2 clinical trial. The Lancet, 383 (9923), 1129-1137. (doi:10.1016/S0140-6736(13)62117-0). (PMID:24439297)

Record type: Article

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

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e-pub ahead of print date: January 2014
Published date: March 2014
Additional Information: Open Access funded by the Wellcome Trust
Organisations: Clinical & Experimental Sciences

Identifiers

Local EPrints ID: 367809
URI: https://eprints.soton.ac.uk/id/eprint/367809
ISSN: 0140-6736
PURE UUID: b143e12e-0f9b-4488-8288-882c036cefe1
ORCID for A.J. Lotery: ORCID iD orcid.org/0000-0001-5541-4305

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Date deposited: 18 Aug 2014 10:22
Last modified: 12 Nov 2019 01:49

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Contributors

Author: R.E. McLaren
Author: M. Groppe
Author: A.R. Barnard
Author: C.L. Cottriall
Author: T. Tolmachova
Author: L. Seymour
Author: K.R. Clark
Author: M.J. During
Author: F.P. Cremers
Author: G.C. Black
Author: A.J. Lotery ORCID iD
Author: S.M. Downes
Author: A.R. Webster
Author: M.C. Seabra

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