July 2018
Volume 59, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2018
First Gene Supplementation Therapy for CNGA3-linked Achromatopsia
Author Affiliations & Notes
  • M Dominik Fischer
    University Eye Hospital, Centre for Ophthalmology, University Hospital of Tübingen, Tübingen, Germany
    Institute for Ophthalmic Research, Centre for Ophthalmology, Eberhard Karls 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-University of Munich, Munich, Germany
  • Barbara Wilhelm
    STZ eyetrial at the Centre for Ophthalmology, University Hospital Tübingen, Tübingen, Germany
  • Nadine Kahle
    STZ eyetrial at the Centre for Ophthalmology, University Hospital Tübingen, Tübingen, Germany
  • Tobias Peters
    STZ eyetrial at the Centre for Ophthalmology, University Hospital Tübingen, Tübingen, Germany
  • Karl Ulrich Bartz-Schmidt
    University Eye Hospital, Centre for Ophthalmology, University Hospital of Tübingen, Tübingen, Germany
  • Susanne Kohl
    Institute for Ophthalmic Research, Centre for Ophthalmology, Eberhard Karls University of Tübingen, Tübingen, Germany
  • Mathias W Seeliger
    Institute for Ophthalmic Research, Centre for Ophthalmology, Eberhard Karls University of Tübingen, Tübingen, Germany
  • Nicole Weisschuh
    Institute for Ophthalmic Research, Centre for Ophthalmology, Eberhard Karls University of Tübingen, Tübingen, Germany
  • Ditta Zobor
    Institute for Ophthalmic Research, Centre for Ophthalmology, Eberhard Karls University of Tübingen, Tübingen, Germany
  • Eberhart Zrenner
    Institute for Ophthalmic Research, Centre for Ophthalmology, Eberhard Karls University of Tübingen, Tübingen, Germany
  • Marius Ueffing
    Institute for Ophthalmic Research, Centre for Ophthalmology, Eberhard Karls 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-University of Munich, Munich, Germany
  • Bernd Wissinger
    Institute for Ophthalmic Research, Centre for Ophthalmology, Eberhard Karls University of Tübingen, Tübingen, Germany
  • Footnotes
    Commercial Relationships   M Dominik Fischer, None; Stylianos Michalakis, Eyeserve (P); Barbara Wilhelm, None; Nadine Kahle, None; Tobias Peters, None; Karl Ulrich Bartz-Schmidt, None; Susanne Kohl, None; Mathias Seeliger, Eyeserve (P); Nicole Weisschuh, None; Ditta Zobor, None; Eberhart Zrenner, None; Marius Ueffing, None; Martin Biel, Eyeserve (P); Bernd Wissinger, None
  • Footnotes
    Support  Tistou und Charlotte Kerstan Stiftung
Investigative Ophthalmology & Visual Science July 2018, Vol.59, 2982. doi:
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    • Get Citation

      M Dominik Fischer, Stylianos Michalakis, Barbara Wilhelm, Nadine Kahle, Tobias Peters, Karl Ulrich Bartz-Schmidt, Susanne Kohl, Mathias W Seeliger, Nicole Weisschuh, Ditta Zobor, Eberhart Zrenner, Marius Ueffing, Martin Biel, Bernd Wissinger; First Gene Supplementation Therapy for CNGA3-linked Achromatopsia. Invest. Ophthalmol. Vis. Sci. 2018;59(9):2982.

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

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Abstract

Purpose : To proof the safety and efficacy of the first gene therapy targeting cone photoreceptors in man.

Methods : Nine patients with CNGA3-linked achromatopsia received a single subfoveal injection of rAAV.hCNGA3 in an open label, monocentric, exploratory, dose-escalation trial (NCT02610582). Three patients were treated per dose group (1x1010, 5x1010, and 1x1011 vector genomes). Safety of application as primary endpoint was assessed by clinical examination and best corrected visual acuity (BCVA), vital signs, blood chemistry (CRP, ESR, blood counts), and immunopathology assays over a period of 12 months. Biodistribution/shedding was monitored in blood, urine, saliva and lacrimal fluid.

Results : The primary endpoint was met with an excellent safety profile of AAV8.hCNGA3 delivered in the subretinal space. Surprisingly, BCVA increased slightly despite foveal detachment (-0.05±0.02 logMAR [mean±se; p = 0.038]). No serious adverse event occurred. Ocular adverse events (AEs) were either unrelated or associated with the surgical procedure, but not the study drug. There were no unexpected AEs outside side effect profile of the study procedure and study drug. Analysis of vital signs, blood chemistry, immunopathology and shedding corroborate the excellent safety profile.

Conclusions : The first clinical gene therapy for achromatopsia in man was well tolerated and did not lead to unexpected (serious) adverse events. Even though the study was not designed and powered to demonstrate efficacy, exploration of endpoints support the notion that CNGA3 linked achromatopsia can be treated by gene supplementation therapy.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.

 

Intraoperative OCT was used to guide and confirm injection in the subretinal space. Here, the initial phase just prior to the foveal detachment is shown.

Intraoperative OCT was used to guide and confirm injection in the subretinal space. Here, the initial phase just prior to the foveal detachment is shown.

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