September 2016
Volume 57, Issue 12
Open Access
ARVO Annual Meeting Abstract  |   September 2016
Successful delivery of rAAV8.CNGA3 in a patient with CNGA3 achromatopsia
Author Affiliations & Notes
  • M Dominik Fischer
    University Eye Hospital, Centre for Ophthalmology Tübingen, University of Tübingen, Tübingen, Germany
    Institute for Ophthalmic Research, Centre for Ophthalmology, University of Tübingen, Tübingen, Germany
  • Barbara Wilhelm
    STZ eyetrial at the Centre for Ophthalmology, University of Tübingen, Tübingen, Germany
  • Stylianos Michalakis
    Center for Integrated Protein Science Munich (CIPSM) at the Department of Pharmacy - Center for Drug Research, Ludwig-Maximilians-Universität München, München, Germany
  • Ditta Zobor
    University Eye Hospital, Centre for Ophthalmology Tübingen, University of Tübingen, Tübingen, Germany
  • Susanne Kohl
    Institute for Ophthalmic Research, Centre for Ophthalmology, University of Tübingen, Tübingen, Germany
  • Matthias Seeliger
    Institute for Ophthalmic Research, Centre for Ophthalmology, University of Tübingen, Tübingen, Germany
  • Eberhart Zrenner
    University Eye Hospital, Centre for Ophthalmology Tübingen, University of Tübingen, Tübingen, Germany
    Institute for Ophthalmic Research, Centre for Ophthalmology, University of Tübingen, Tübingen, Germany
  • Marius Ueffing
    Institute for Ophthalmic Research, Centre for Ophthalmology, University of Tübingen, Tübingen, Germany
  • Bernd Wissinger
    Institute for Ophthalmic Research, Centre for Ophthalmology, University of Tübingen, Tübingen, Germany
  • Martin Biel
    Center for Integrated Protein Science Munich (CIPSM) at the Department of Pharmacy - Center for Drug Research, Ludwig-Maximilians-Universität München, München, Germany
  • Karl Ulrich Bartz-Schmidt
    University Eye Hospital, Centre for Ophthalmology Tübingen, University of Tübingen, Tübingen, Germany
  • Footnotes
    Commercial Relationships   M Dominik Fischer, None; Barbara Wilhelm, None; Stylianos Michalakis, None; Ditta Zobor, None; Susanne Kohl, None; Matthias Seeliger, None; Eberhart Zrenner, None; Marius Ueffing, None; Bernd Wissinger, None; Martin Biel, None; Karl Ulrich Bartz-Schmidt, None
  • Footnotes
    Support  Tistou & Charlotte Kerstan Stiftung
Investigative Ophthalmology & Visual Science September 2016, Vol.57, No Pagination Specified. doi:
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      M Dominik Fischer, Barbara Wilhelm, Stylianos Michalakis, Ditta Zobor, Susanne Kohl, Matthias Seeliger, Eberhart Zrenner, Marius Ueffing, Bernd Wissinger, Martin Biel, Karl Ulrich Bartz-Schmidt; Successful delivery of rAAV8.CNGA3 in a patient with CNGA3 achromatopsia. Invest. Ophthalmol. Vis. Sci. 201657(12):.

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      © 2017 Association for Research in Vision and Ophthalmology.

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Abstract

Purpose : The aim of this clinical interventional study (NCT02610582) was to test safety aspects of AAV8 based supplementation gene therapy in patients with CNGA3 achromatopsia.

Methods : After extensive safety testing in a dose escalation study in 34 non-human primates (NHP), we selected a dosing range of 1x1010, 5x1010, and 1x1011 vector genomes (vg) for an exploratory, dose-escalation clinical phase I/II trial. A first patient with homozygous mutations in CNGA3 received a single subretinal injection of 1x1010 vg in 0.2ml balanced salt solution. Concomitant steroid treatment (Prednisolone 1mg/kg/d) was initiated 1 day prior surgery. The primary endpoint - safety of application - was assessed by clinical examination and best corrected visual acuity (BCVA).

Results : NHP safety data showed no persisting test item-related changes after application of ≤ 1x1012 vg 90 days after dosing. In the clinical trial, the first patient received the low dose (1x1010 vg) safely and without surgical or post-surgical complications such as retinal detachment, haemorrhage or inflammation unresponsive to treatment. BCVA reached baseline levels as soon as 14 days post treatment. Structural changes at the level of the retinal pigment epithelium and inner/outer photoreceptor segments as tested by optical coherence tomography were attributed to the surgical procedure.

Conclusions : The NHP safety study showed that ≤ 1x1012 vg could be applied without relevant sequelae. The first clinical gene therapy for achromatopsia in man was well tolerated and did not lead to clinically apparent inflammation under concomitant Prednisolone treatment. Even though the application involved macular detachment, visual acuity reached baseline levels within 14 days.

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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