June 2023
Volume 64, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2023
Delivering topical IL-33 mRNA + nanoparticles to treat neovascular age-related macular degeneration.
Author Affiliations & Notes
  • Lisa J Hill
    University of Birmingham College of Medical and Dental Sciences, Birmingham, Birmingham, United Kingdom
  • Chloe Thomas
    University of Birmingham College of Medical and Dental Sciences, Birmingham, Birmingham, United Kingdom
  • Alison Clare
    University of Bristol, Bristol, Bristol, United Kingdom
  • Lynn Jena
    Queen's University Belfast, Belfast, Belfast, United Kingdom
  • Chris Weston
    University of Birmingham College of Medical and Dental Sciences, Birmingham, Birmingham, United Kingdom
  • Eleanor Hickman
    University of Birmingham College of Medical and Dental Sciences, Birmingham, Birmingham, United Kingdom
  • Jamie Cowley
    University of Birmingham College of Medical and Dental Sciences, Birmingham, Birmingham, United Kingdom
  • Alastair K Denniston
    University of Birmingham College of Medical and Dental Sciences, Birmingham, Birmingham, United Kingdom
  • Andrew D Dick
    University of Bristol, Bristol, Bristol, United Kingdom
  • Dave A Copland
    University of Bristol, Bristol, Bristol, United Kingdom
  • Helen O McCarthy
    Queen's University Belfast, Belfast, Belfast, United Kingdom
  • Footnotes
    Commercial Relationships   Lisa Hill None; Chloe Thomas None; Alison Clare None; Lynn Jena None; Chris Weston None; Eleanor Hickman None; Jamie Cowley None; Alastair Denniston None; Andrew Dick University of Bristol, Code P (Patent); Dave Copland None; Helen McCarthy pHion Therapeutics , Code P (Patent)
  • Footnotes
    Support  FFS Grant Ref 5093/5094
Investigative Ophthalmology & Visual Science June 2023, Vol.64, 930. doi:
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    • Get Citation

      Lisa J Hill, Chloe Thomas, Alison Clare, Lynn Jena, Chris Weston, Eleanor Hickman, Jamie Cowley, Alastair K Denniston, Andrew D Dick, Dave A Copland, Helen O McCarthy; Delivering topical IL-33 mRNA + nanoparticles to treat neovascular age-related macular degeneration.. Invest. Ophthalmol. Vis. Sci. 2023;64(8):930.

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

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Abstract

Purpose : Age-related macular degeneration (AMD) is the most common cause of central vision loss globally. Patients with nAMD treated with regular intraocular injections of anti-VEGF therapies, to which some patients are unresponsive, exhibit non-compliance and risk complications. Interleukin-33 (IL-33) is a promising new treatment for AMD. We have investigated complexion, transfection efficiency and ocular penetration of our interleukin-33 (IL-33) mRNA nanoparticle (NP) eye drop to treat nAMD.

Methods : We tested IL-33 mRNA+NP (500ng mRNA) complexion using zeta potentials. Transfection efficiency was tested in vitro with nanoparticles (N:P 6,8,10) in ARPE-19 and human ocular choroidal fibroblasts (HOCFs) using GFP mRNA+NP and measured FITC+ using flow cytometry. We tested cell toxicity and viability using MTT and LDH assays. We tested the penetration of our eye drop in ex vivo porcine assay and in vivo mouse eyes, 1h after applying 500ng of mRNA therapeutic by quantifying distribution in the vitreous and retina/RPE/sclera using RT-PCR.

Results : We have shown successful complexion of IL-33 mRNA+NP through high charge and small diameter, with a mean diameter of 114.6 ± 10.1 nm (± SD), zeta potential charge of 15.7 ± 5 mV for N:P 10. There was successful translation of our GFP mRNA+NP in ARPE-19 and HOCFs, with the greatest FITC+ cells with N:P 10 of our NPs (4.56% ± 0.29% FITC+ cells compared to 0.09% ± 0.01% in cells treated with GFP mRNA alone, P<0.0001). We show no toxicity with our mRNA+NP complexes. Excitingly, we have shown penetration of our IL-33 mRNA+NP into the vitreous (~0.5pg) and retina (~0.2pg) of an ex vivo porcine eye. In the mouse eye in vivo, we detected 2.45±3.34 ng of IL-33 mRNA when applied as a topical IL-33 mRNA+NP treatment compared to 0.23±0.18 ng detected in EGFP mRNA+NP control group (unpaired t-test P=0.881). High levels of IL-33 mRNA was detected in eyes receiving intravitreal injection of IL-33 mRNA+NP (16.71±3.69ng) which was considerably less when IL-33 mRNA was uncomplexed (0.0043±0.001ng), suggesting that our NP protects the mRNA from degradation.

Conclusions : Our IL-33 mRNA+NP immunotherapeutic offers an exciting new topical therapeutic for AMD and offers the potential for delivery to the retina/RPE/choroid. Further experiments will test our IL-33 mRNA+NP in a mouse in vivo L-CNV model.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.

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