September 2016
Volume 57, Issue 12
Open Access
ARVO Annual Meeting Abstract  |   September 2016
Long term vision results following retinal gene therapy for choroideremia
Author Affiliations & Notes
  • Robert E MacLaren
    Nuffield Laboratory of Ophthalmology, University of Oxford, Oxford, Oxfordshire, United Kingdom
    Oxford University Hospitals NHS Foundation Trust, Oxford Eye Hospital, Oxford, United Kingdom
  • Thomas L Edwards
    Nuffield Laboratory of Ophthalmology, University of Oxford, Oxford, Oxfordshire, United Kingdom
    Oxford University Hospitals NHS Foundation Trust, Oxford Eye Hospital, Oxford, United Kingdom
  • Jasleen Jolly
    Nuffield Laboratory of Ophthalmology, University of Oxford, Oxford, Oxfordshire, United Kingdom
    Oxford University Hospitals NHS Foundation Trust, Oxford Eye Hospital, Oxford, United Kingdom
  • Alun R Barnard
    Nuffield Laboratory of Ophthalmology, University of Oxford, Oxford, Oxfordshire, United Kingdom
  • Kanmin Xue
    Nuffield Laboratory of Ophthalmology, University of Oxford, Oxford, Oxfordshire, United Kingdom
    Oxford University Hospitals NHS Foundation Trust, Oxford Eye Hospital, Oxford, United Kingdom
  • Susan Downes
    Nuffield Laboratory of Ophthalmology, University of Oxford, Oxford, Oxfordshire, United Kingdom
    Oxford University Hospitals NHS Foundation Trust, Oxford Eye Hospital, Oxford, United Kingdom
  • Graham E Holder
    UCL Institute of Ophthalmology, London, United Kingdom
    Moorfields Eye Hospital, London, United Kingdom
  • Graeme C.M. Black
    University of Manchester, Manchester, United Kingdom
  • Andrew J Lotery
    University of Southampton, Southampton, United Kingdom
  • Andrew Webster
    UCL Institute of Ophthalmology, London, United Kingdom
    Moorfields Eye Hospital, London, United Kingdom
  • Miguel Seabra
    NHLI Imperial College, London, United Kingdom
    CEDOC Nova Medical School, Lisbon, Portugal
  • Footnotes
    Commercial Relationships   Robert MacLaren, Nightstarx Ltd (C), Nightstarx Ltd (I), NIghtstarx Ltd (F), University of Oxford (P), University of Oxford (E), Wellcome Trust (F); Thomas Edwards, None; Jasleen Jolly, None; Alun Barnard, None; Kanmin Xue, None; Susan Downes, None; Graham Holder, None; Graeme Black, None; Andrew Lotery, None; Andrew Webster, Nightstarx Ltd (F); Miguel Seabra, Nightstarx Ltd (I), NIghtstarx Ltd (C), University of Oxford (P)
  • Footnotes
    Support  UK Department of Health and the Wellcome Trust Health Innovation Challenge Fund (HICF), Fight for Sight, Royal College of Surgeons of Edinburgh, Oxford and Moorfields NIHR Biomedical Research Centres
Investigative Ophthalmology & Visual Science September 2016, Vol.57, No Pagination Specified. doi:
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      Robert E MacLaren, Thomas L Edwards, Jasleen Jolly, Alun R Barnard, Kanmin Xue, Susan Downes, Graham E Holder, Graeme C.M. Black, Andrew J Lotery, Andrew Webster, Miguel Seabra; Long term vision results following retinal gene therapy for choroideremia. Invest. Ophthalmol. Vis. Sci. 201657(12):.

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

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Abstract

Purpose : The long term stability of visual function improvements following retinal gene therapy for Leber congenital amaurosis using adeno-associated viral (AAV) vectors has recently been questioned. We therefore sought to determine the long term effects of AAV retinal gene therapy for choroideremia in the first six patients undergoing treatment for this condition.

Methods : Patients were recruited into an open label dose escalation study (NCT01461213). An AAV2 vector encoding the choroideremia gene and a Woodchuck hepatitis virus post-transcriptional regulatory element (AAV.CHM.WPRE) was injected subretinally at a dose of 1010 genome particles (gp) in five patients (P1-5) and 0.6x109 in P6. Visual acuity (VA) was measured using the Early Treatment for Diabetic Retinopathy study (ETDRS) charts. Microperimetery was measured in mean decibels (dB).

Results : For the five patients receiving 1010 gp of AAV.CHM.WPRE, the mean ETDRS VA change at 2 years was +4.4±4.2 letters in the treated eyes and -2.4±1.9 letters in the unoperated control eyes. At the last follow up timepoint at 3.5 years (after cataract surgery in 3 of 5 patients), the mean (±SEM) VA change was +8.4±4.7 letters in the treated eyes and -8.8±3.1 letters in the control eyes, equivalent to a mean difference of over three ETDRS lines. The treated eyes had become dominant in all five of these patients. P6 who received a lower dose of 6x109 gp showed a steady decline in VA in both eyes, losing 29 and 18 letters in his treated and untreated control eyes, respectively. By 4 years, P1 who has not yet undergone cataract surgery, had a sustained gain of 22 letters in his treated eye with loss of 26 letters in his control eye - a relative change of approximately 10 ETDRS lines between the two eyes over this time. Microperimetry was broadly similar, with mean changes of -0.7±0.4 dB and -2.0±0.6 dB in the treated and untreated eyes of P1-5 respectively at 2 years. An improvement in the pattern electroretinogram (PERG) was seen only in the treated eye of P3, the patient with the best baseline visual function.

Conclusions : Early VA improvements noted in two patients following gene therapy were sustained for up to 4 years. Three further patients who had near maximal VA in their treated eyes at baseline maintained it, despite losing VA in their unoperated eyes over this time. One patient did not show any apparent response to gene therapy at the 6 x 109 gp dose.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.

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