June 2022
Volume 63, Issue 7
Open Access
ARVO Annual Meeting Abstract  |   June 2022
A Novel Bi-cistronic Gene Therapy for Neovascular Age-Related Macular Degeneration in Patients with Developing Subretinal Fibrosis
Author Affiliations & Notes
  • Andrew Osborne
    Ikarovec Limited, Norwich, United Kingdom
  • Emily Francesca Warner
    Ikarovec Limited, Norwich, United Kingdom
  • Kara Boyd
    Ikarovec Limited, Norwich, United Kingdom
  • Peter Stuart Widdowson
    Ikarovec Limited, Norwich, United Kingdom
  • Katie Binley
    Ikarovec Limited, Norwich, United Kingdom
  • Footnotes
    Commercial Relationships   Andrew Osborne Ikarovec Limited, Code E (Employment); Emily Warner Ikarovec Limited, Code E (Employment); Kara Boyd Ikarovec Limited, Code E (Employment); Peter Widdowson Ikarovec Limited, Code E (Employment), Ikarovec Limited, Code O (Owner), Ikarovec Limited, Code P (Patent), Ikarovec Limited, Code S (non-remunerative); Katie Binley Ikarovec Limited, Code E (Employment), Ikarovec Limited, Code P (Patent)
  • Footnotes
    Support  UKI2S/InnovateUK
Investigative Ophthalmology & Visual Science June 2022, Vol.63, 52 – A0025. doi:
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    • Get Citation

      Andrew Osborne, Emily Francesca Warner, Kara Boyd, Peter Stuart Widdowson, Katie Binley; A Novel Bi-cistronic Gene Therapy for Neovascular Age-Related Macular Degeneration in Patients with Developing Subretinal Fibrosis. Invest. Ophthalmol. Vis. Sci. 2022;63(7):52 – A0025.

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

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Abstract

Purpose : Anti-VEGF therapies for neovascular age-related macular degeneration (nAMD) have significantly revolutionised outcomes for millions of people. However, anti-VEGF drug efficacy and vision deteriorates in a significant proportion of individuals due to subretinal fibrosis. We designed a gene therapy capable of preventing, or reversing, subretinal fibrosis and neutralising pathological VEGF concentrations responsible for neovascularisation.

Methods : Bi-cistronic plasmids and rAAV2/2 vector constructs expressing both anti-VEGF and anti-fibrotic components were examined in HEK293T, ARPE-19 cells and on co-cultures of human fibroblast/HUVECs. The lead constructs were evaluated in rodent models.

Results : The lead constructs express a novel anti-VEGF capture protein that has a reduced affinity for human IgG-Fc gamma receptors than aflibercept. The constructs reduce endogenous VEGF concentrations (ng/mL) in HEK293Ts (control Null plasmid = 663 ± 15, IKC116P = 275 ± 7***, aflibercept = 296 ± 4***; P<0.001 by ANOVA followed by Bonferroni modified t-tests, mean ± SEM of 3 replicates) and attenuates capillary formation in co-cultures with equivalent efficacy to aflibercept. The anti-fibrotic component attenuates transforming growth factor (TGF)-beta-induced epithelial-mesenchymal transition, a precursor to subretinal fibrotic scar formation, as shown by the reduction in ARPE-19 fibronectin (control Null plasmid = 2.64 ± 0.32, IKC116P = 1.96 ± 0.26; P<0.05, n=4) and release of matrix metalloprotease-2 (control Null plasmid = 1.46 ± 0.09, IKC116P = 0.28 ± 0.04; P<0.0001, n=4) by western blot. Intravitreal injection of the lead vectors completely prevented vascular leakage after laser-induced CNV in mice compared to the vehicle controls.

Conclusions : The novel anti-VEGF component is equipotent to aflibercept in VEGF neutralisation. Moreover, the incorporation of an anti-fibrotic transgene reduced TGF-beta induced early scar formation in ARPE-19 cells. This bi-cistronic gene therapy has the potential to address subretinal fibrosis in patients with deteriorating vision currently treated with anti-VEGF therapies.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.

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