March 2012
Volume 53, Issue 14
Free
ARVO Annual Meeting Abstract  |   March 2012
Gene Therapy For Choroideremia - Initial Report On A New Clinical Trial
Author Affiliations & Notes
  • Robert E. MacLaren
    Nuffield Laboratory of Ophthalmology, University of Oxford, Oxford, United Kingdom
    Moorfields Eye Hospital NHS Foundation Trust, London, United Kingdom
  • Markus Groppe
    Nuffield Laboratory of Ophthalmology, University of Oxford, Oxford, United Kingdom
  • Alun R. Barnard
    Nuffield Laboratory of Ophthalmology, University of Oxford, Oxford, United Kingdom
  • Tanya Tolmachova
    Molecular Medicine, Imperial College London, London, United Kingdom
  • Matthew J. During
    Ohio State University Medical Center, Columbus, Ohio
  • Susan M. Downes
    Oxford Eye Hospital, Oxford University Hospitals NHS Trust, Oxford, United Kingdom
  • Andrew J. Lotery
    Ophthalmology - Eye Unit, Southampton General Hospital, Southampton, United Kingdom
  • Graeme C. Black
    Genetic Medicine, University of Manchester, Manchester, United Kingdom
  • Andrew R. Webster
    Moorfields Eye Hospital NHS Foundation Trust, London, United Kingdom
    UCL Institute of Ophthalmology, London, United Kingdom
  • Miguel C. Seabra
    Molecular Medicine, Imperial College London, London, United Kingdom
  • Footnotes
    Commercial Relationships  Robert E. MacLaren, Named inventor on UK patent application 1103062.4 filed on behalf of the University of Oxford (P); Markus Groppe, None; Alun R. Barnard, None; Tanya Tolmachova, None; Matthew J. During, Named inventor on UK patent application 1103062.4 filed on behalf of the University of Oxford (P); Susan M. Downes, None; Andrew J. Lotery, None; Graeme C. Black, None; Andrew R. Webster, None; Miguel C. Seabra, Named inventor on UK patent application 1103062.4 filed on behalf of the University of Oxford (P)
  • Footnotes
    Support  Wellcome Trust, UK Department of Health, NIHR Biomedical Research Centres, Health Innovation Challenge Fund, Fight for Sight, Royal College of Surgeons of Edinburgh
Investigative Ophthalmology & Visual Science March 2012, Vol.53, 5577. doi:https://doi.org/
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      Robert E. MacLaren, Markus Groppe, Alun R. Barnard, Tanya Tolmachova, Matthew J. During, Susan M. Downes, Andrew J. Lotery, Graeme C. Black, Andrew R. Webster, Miguel C. Seabra; Gene Therapy For Choroideremia - Initial Report On A New Clinical Trial. Invest. Ophthalmol. Vis. Sci. 2012;53(14):5577. doi: https://doi.org/.

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

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Abstract
 
Purpose:
 

To report the initial findings from a new clinical trial using gene therapy with an adeno-associated viral (AAV) vector encoding Rab escort protein-1 (REP1) to treat patients suffering from choroideremia (NCT01461213).

 
Methods:
 

An AAV2 vector encoding human REP1 driven by a CBA promoter with a woodchuck hepatitis virus post-translational regulatory element (WPRE) was made to Good Medical Practice (GMP) standards and approved for clinical use by the UK Medicines and Healthcare products Regulatory Authority (MHRA). The final vector solution was 1 x 10e12 genome particles (gp) per ml, in 0.001% PF68 surfactant. Two cohorts each of six patients will receive a total dose of 1 x 10e10 gp or 1 x 10e11 gp delivered by subretinal injection. Disease status is measured at baseline using microperimetry, electroretinography, autofluorescence and spectral domain optical coherence tomography (OCT). The primary end point is delivery of vector without complications and the secondary endpoint is measurement of choroidal shrinkage compared to the control eye.

 
Results:
 

Preclinical testing revealed that surfactant was essential to prevent loss of AAV particles in the plastic injection system. In the first patient to be treated, the retina overlying a residual central island of choroid was detached in a controlled two step procedure, which created a space into which 0.1 ml of the AAV vector suspension was injected through a 41 gauge teflon needle on a 23 gauge cannula. Subretinal fluid was evident at post-operative day one, but had reabsorbed by one week. By one month best corrected visual acuity had returned to at least baseline levels.

 
Conclusions:
 

In choroideremia the retina can be detached for subretinal injection of an AAV vector expressing REP1 with no immediately obvious detrimental effects on structure or function. The global deficiency of the RPE and choroid does not appear to inhibit reabsorption of subretinal fluid. Choroideremia appears to be a good candidate disease for gene replacement therapy. High resolution clinical imaging tests will require several months to determine whether or not sight loss can be prevented.  

 
Clinical Trial:
 

http://www.clinicaltrials.gov NCT01461213

 
Keywords: clinical (human) or epidemiologic studies: treatment/prevention assessment/controlled clinical trials • gene transfer/gene therapy • retinal degenerations: hereditary 
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