April 2014
Volume 55, Issue 13
Free
ARVO Annual Meeting Abstract  |   April 2014
Improved visual function in patients with choroideremia undergoing subretinal gene therapy
Author Affiliations & Notes
  • Robert E MacLaren
    Nuffield Laboratory of Ophthalmology, University of Oxford, Oxford, United Kingdom
    Oxford Eye Hospital, Oxford University Hospitals NHS Trust, Oxford, United Kingdom
  • Markus Groppe
    Nuffield Laboratory of Ophthalmology, University of Oxford, Oxford, United Kingdom
    Oxford Eye Hospital, Oxford University Hospitals NHS Trust, Oxford, United Kingdom
  • Alun R Barnard
    Nuffield Laboratory of Ophthalmology, University of Oxford, Oxford, United Kingdom
  • Tanya Tolmachova
    Molecular Medicine, NHLI, Imperial College School of Medicine, London, United Kingdom
  • Frans P Cremers
    Department of Human Genetics, Radboud University Medical Centre, Nijmegen, Netherlands
  • Graeme C Black
    Department of Genetics, University of Manchester, Manchester, United Kingdom
  • Andrew Lotery
    Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom
  • Susan M Downes
    Nuffield Laboratory of Ophthalmology, University of Oxford, Oxford, United Kingdom
    Oxford Eye Hospital, Oxford University Hospitals NHS Trust, Oxford, United Kingdom
  • Andrew Webster
    Moorfields Eye Hospital, London, United Kingdom
  • Miguel C Seabra
    Molecular Medicine, NHLI, Imperial College School of Medicine, London, United Kingdom
    Faculdade de Ciencias Medicas, Universidade Nova de Lisboa, Lisbon, Portugal
  • Footnotes
    Commercial Relationships Robert MacLaren, University of Oxford (P); Markus Groppe, None; Alun Barnard, None; Tanya Tolmachova, None; Frans Cremers, None; Graeme Black, None; Andrew Lotery, None; Susan Downes, None; Andrew Webster, None; Miguel Seabra, University of Oxford (P)
  • Footnotes
    Support None
Investigative Ophthalmology & Visual Science April 2014, Vol.55, 832. doi:
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      Robert E MacLaren, Markus Groppe, Alun R Barnard, Tanya Tolmachova, Frans P Cremers, Graeme C Black, Andrew Lotery, Susan M Downes, Andrew Webster, Miguel C Seabra, ; Improved visual function in patients with choroideremia undergoing subretinal gene therapy. Invest. Ophthalmol. Vis. Sci. 2014;55(13):832.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract
 
Purpose
 

To report the results of a gene therapy clinical trial using an adeno-associated viral (AAV) vector encoding Rab escort protein (REP)1 in six patients with a diagnosis of choroideremia.

 
Methods
 

An AAV vector (serotype 2) was constructed with a modified CBA promoter that incorporated a synthetic intron upstream of the gene encoding REP1, coupled downstream to a modified Woodchuck hepatitis virus post-transcriptional regulatory element (WPRE) and bovine polyA signal. After 23 gauge pars plana vitrectomy, the vector was delivered by subretinal injection in 6 patients with choroideremia at a dose of 1010 genome particles (gp) in five patients and 6 x 109 in the sixth. The foveal region was detached in all patients, four of whom had per-operative vision of 20/30 or better. Visual function was assessed with visual acuity (VA) and microperimetry at baseline followed by 6 months and one year post-surgery. Anatomical changes were assessed with optical coherence tomography and autofluorescence.

 
Results
 

Six months after surgery, the visual acuity improved by two lines and four lines in the two patients in whom VA was less than 20/30 at baseline - this improvement was sustained at one year. VA returned to within one line of baseline in the other four patients. Despite undergoing foveal detachment, there was a mean improvement in retinal sensitivity in the treated eyes (+0.63 dB) compared to the control eyes (-0.60 dB) one year after gene therapy (95% confidence interval of difference: +0.05 to +2.40 dB). Within this group, improvements in retinal sensitivity were correlated to the total dose of vector administered per mm2 of retina measured by autofluorescence. Mild progression of cataract was noted in treated eyes but in contrast to previous studies, no significant retinal thinning was observed.

 
Conclusions
 

Improvements in retinal sensitivity and visual acuity were observed at six months and sustained for up to one year in choroideremia patients undergoing retinal gene therapy. Since foveal detachment, post-vitrectomy cataract and progressive retinal degeneration would ordinarily be associated with a reduction in vision over this period, the sustained improvements seen show the potential of gene replacement therapy when applied before the onset of foveal thinning and validate the concept of subretinal gene delivery predicted by the preclinical studies over recent years.

 
 
Gene therapy for chroideremia
 
Gene therapy for chroideremia
 
Keywords: 696 retinal degenerations: hereditary • 538 gene transfer/gene therapy • 648 photoreceptors  
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