July 2019
Volume 60, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2019
Effects of Subretinal AAV8 Gene Therapy on Microperimetry in CNGA3 Achromatopsia Patients
Author Affiliations & Notes
  • G. Alex Ochakovski
    Centre for Ophthalmology, University Eye Hospital, University Hospital Tuebingen, Tuebingen, Germany
  • Ahmad Zhour
    Centre for Ophthalmology, University Eye Hospital, University Hospital Tuebingen, Tuebingen, Germany
  • Laura Kuehlewein
    Centre for Ophthalmology, University Eye Hospital, University Hospital Tuebingen, Tuebingen, Germany
  • Susanne Kohl
    Institute for Ophthalmic Research, Centre for Ophthalmology, University Hospital Tuebingen, Tuebingen, Germany
  • Andrea Rindtorff
    STZ eyetrial at the Centre for Ophthalmology, University Hospital Tuebingen, Tuebingen, Germany
  • Karl Ulrich Bartz-Schmidt
    Centre for Ophthalmology, University Eye Hospital, University Hospital Tuebingen, Tuebingen, Germany
  • Marius Ueffing
    Institute for Ophthalmic Research, Centre for Ophthalmology, University Hospital Tuebingen, Tuebingen, Germany
  • Eberhart Zrenner
    Centre for Ophthalmology, University Eye Hospital, University Hospital Tuebingen, Tuebingen, Germany
    Institute for Ophthalmic Research, Centre for Ophthalmology, University Hospital Tuebingen, Tuebingen, 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
  • 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, University Hospital Tuebingen, Tuebingen, Germany
  • Tobias Peters
    STZ eyetrial at the Centre for Ophthalmology, University Hospital Tuebingen, Tuebingen, Germany
  • Barbara Wilhelm
    STZ eyetrial at the Centre for Ophthalmology, University Hospital Tuebingen, Tuebingen, Germany
  • M. Dominik Fischer
    Centre for Ophthalmology, University Eye Hospital, University Hospital Tuebingen, Tuebingen, Germany
    Institute for Ophthalmic Research, Centre for Ophthalmology, University Hospital Tuebingen, Tuebingen, Germany
  • Footnotes
    Commercial Relationships   G. Alex Ochakovski, None; Ahmad Zhour, None; Laura Kuehlewein, None; Susanne Kohl, None; Andrea Rindtorff, None; Karl Ulrich Bartz-Schmidt, None; Marius Ueffing, None; Eberhart Zrenner, None; Stylianos Michalakis, Eyeserv GmbH (P); Martin Biel, Eyeserv GmbH (P); Bernd Wissinger, None; Tobias Peters, None; Barbara Wilhelm, None; M. Dominik Fischer, None
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science July 2019, Vol.60, 2921. doi:https://doi.org/
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      G. Alex Ochakovski, Ahmad Zhour, Laura Kuehlewein, Susanne Kohl, Andrea Rindtorff, Karl Ulrich Bartz-Schmidt, Marius Ueffing, Eberhart Zrenner, Stylianos Michalakis, Martin Biel, Bernd Wissinger, Tobias Peters, Barbara Wilhelm, M. Dominik Fischer; Effects of Subretinal AAV8 Gene Therapy on Microperimetry in CNGA3 Achromatopsia Patients. Invest. Ophthalmol. Vis. Sci. 2019;60(9):2921. doi: https://doi.org/.

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

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Abstract

Purpose : Mutations in the gene encoding the cyclic nucleotide-gated channel subunit alpha 3 (CNGA3) are a major cause for achromatopsia (ACHM), a genetic disease characterized by photophobia, reduced visual acuity and nystagmus due to an impairment of cone photoreceptor function. We measured the effects of recombinant adeno-associated virus serotype 8 (AAV8) encoding human CNGA3 (rAAV8.hCNGA3) on microperimetry in patients with ACHM.

Methods : In a dose escalation Phase I/II clinical trial, 9 patients with CNGA3-linked ACHM were administered AAV8.CNGA3 (0.1-1.0x1011 vector genomes, vg) via subretinal injection. Changes in visual function from baseline in terms of micro-perimetry were assessed over a period of 12 months post treatment and analyzed using the Visual Field Modeling and Analysis (VFMA) hill of vision approach of the central 10° macular area.

Results : All patients had an excellent safety profile for rAAV8.hCNGA3 after surgery. Although ACHM patients experience no cone-mediated visual cortex stimulation during childhood in ACHM, 5 out of 9 treated patients’ eyes demonstrated some degree of improvement in microperimetry at 12 months post-treatment. The hill of vision volume of the full 10° macular area improved on average by 0.0613 dB-sr (s.d. = 0.098; p = 0.12). The highest improvement of 0.153 dB-sr (s.d. = 0.106) was shown in the intermediate dose (0.5x1011 vg) cohort (n = 3) at month 12.

Conclusions : Subretinal delivery of rAAV8.hCNGA3 has demonstrated an excellent safety profile and some degree of improvement of sensitivity in microperimetry. Best results were obtained in the intermediate dose cohort. However, as the trial was not designed to formally assess efficacy in a dose dependent manner, its limitations include a small sample size. As technical reasons precluded analysis of the treated area specifically, current analysis combines results from treated and untreated macular regions. Trial registration: NCT02610582.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.

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