July 2019
Volume 60, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2019
Development and efficacy assessment of AAV2/8-hG1.7p.coCNGA3, a CNGA3 gene therapy vector
Author Affiliations & Notes
  • Tassos Georgiadis
    MeiraGTx Ltd, London, United Kingdom
    UCL Institute of Ophthalmology, London, United Kingdom
  • Takaaki Matsuki
    UCL Institute of Ophthalmology, London, United Kingdom
  • Justin Hoke
    UCL Institute of Ophthalmology, London, United Kingdom
  • Matteo Rizzi
    UCL Institute of Ophthalmology, London, United Kingdom
  • Anai Gonzalez-Cordero
    UCL Institute of Ophthalmology, London, United Kingdom
  • Robert Sampson
    UCL Institute of Ophthalmology, London, United Kingdom
  • James WB Bainbridge
    UCL Institute of Ophthalmology, London, United Kingdom
    MeiraGTx Ltd, London, United Kingdom
  • Alexander Smith
    UCL Institute of Ophthalmology, London, United Kingdom
    MeiraGTx Ltd, London, United Kingdom
  • Robin R Ali
    UCL Institute of Ophthalmology, London, United Kingdom
    MeiraGTx Ltd, London, United Kingdom
  • Footnotes
    Commercial Relationships   Tassos Georgiadis, MeiraGTx Ltd (E); Takaaki Matsuki, None; Justin Hoke, None; Matteo Rizzi, None; Anai Gonzalez-Cordero, None; Robert Sampson, None; James Bainbridge, MeiraGTx Ltd (C); Alexander Smith, MeiraGTx Ltd (C); Robin Ali, MeiraGTx Ltd (C)
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science July 2019, Vol.60, 3426. doi:
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      Tassos Georgiadis, Takaaki Matsuki, Justin Hoke, Matteo Rizzi, Anai Gonzalez-Cordero, Robert Sampson, James WB Bainbridge, Alexander Smith, Robin R Ali; Development and efficacy assessment of AAV2/8-hG1.7p.coCNGA3, a CNGA3 gene therapy vector. Invest. Ophthalmol. Vis. Sci. 2019;60(9):3426.

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

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Abstract

Purpose : Achromatopsia is an autosomal-recessive retinal condition characterised by intact rod function and absent cone function. CNGA3 mutations are a major cause of achromatopsia. We developed AAV2/8-hG1.7p.coCNGA3, an AAV2/8-based vector, carrying a human codon optimised CNGA3 gene driven by an engineered fragment of human green opsin promoter that leads to rescue of cone function in Cnga3-deficient mice.

Methods : In preparation for a Phase I/II clinical trial, we first assessed the expression profile and efficacy of different human green opsin promoter designs in human iPSC-derived retinal organoids using an in vitro reporter gene assay. In addition, we also assessed the efficacy of either human wild-type CNGA3 or human codon optimised CNGA3 transgenes to improve retinal function in vivo in the Cnga3-deficient mouse model. The most potent promoter version (hG1.7p) and transgene (coCNGA3) were selected and incorporated in an AAV2/8-based vector.

Results : The resulting vector (AAV2/8-hG1.7p.coCNGA3) was used to assess its efficacy in improving cone function in vivo in the Cnga3-deficient mouse at escalating titres that mirror those planned for the clinical trial. Functional assessments were carried out at regular intervals. Visual improvements were long-term and cone photoreceptor survival was sustained up to the latest experimental timepoint at 11 months following subretinal delivery.

Conclusions : Administration of AAV2/8-hG1.7p.coCNGA3 resulted in improvements in cone function in Cnga3-deficient mice at all titres planned for the clinical trial, showing an improved therapeutic response in line with increasing dosage.

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

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