June 2023
Volume 64, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2023
miR-181a/b modulation as potential therapeutic approach for AMD treatment
Author Affiliations & Notes
  • Simona Brillante
    Telethon Institute of Genetics and Medicine, Napoli, Campania, Italy
    Istituto di Ricerca Genetica e Biomedica Consiglio Nazionale delle Ricerche Sede di Milano, Milano, Lombardia, Italy
  • Eva Cipollaro
    Telethon Institute of Genetics and Medicine, Napoli, Campania, Italy
  • Anna Diana
    Telethon Institute of Genetics and Medicine, Napoli, Campania, Italy
  • Marta Molinari
    Telethon Institute of Genetics and Medicine, Napoli, Campania, Italy
  • Mariagrazia Volpe
    Telethon Institute of Genetics and Medicine, Napoli, Campania, Italy
    European School of Molecular Medicine, Milano, Lombardia, Italy
  • Carla Damiano
    Telethon Institute of Genetics and Medicine, Napoli, Campania, Italy
  • Antonietta Tarallo
    Telethon Institute of Genetics and Medicine, Napoli, Campania, Italy
  • Giancarlo Parenti
    Telethon Institute of Genetics and Medicine, Napoli, Campania, Italy
  • Sandro Banfi
    Telethon Institute of Genetics and Medicine, Napoli, Campania, Italy
    Universita degli Studi della Campania Luigi Vanvitelli, Caserta, Campania, Italy
  • Sabrina Carrella
    Stazione Zoologica Anton Dohrn Napoli, Napoli, Campania, Italy
  • Alessia Indrieri
    Telethon Institute of Genetics and Medicine, Napoli, Campania, Italy
    Istituto di Ricerca Genetica e Biomedica Consiglio Nazionale delle Ricerche Sede di Milano, Milano, Lombardia, Italy
  • Footnotes
    Commercial Relationships   Simona Brillante None; Eva Cipollaro None; Anna Diana None; Marta Molinari None; Mariagrazia Volpe None; Carla Damiano None; Antonietta Tarallo None; Giancarlo Parenti None; Sandro Banfi WO/2019/202162, Code P (Patent); Sabrina Carrella WO/2019/202162, Code P (Patent); Alessia Indrieri WO/2019/202162, Code P (Patent)
  • Footnotes
    Support  BFF Grant M2020184; MUR/PRIN2020 Grant 2020XBCMHJ
Investigative Ophthalmology & Visual Science June 2023, Vol.64, 2113. doi:
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    • Get Citation

      Simona Brillante, Eva Cipollaro, Anna Diana, Marta Molinari, Mariagrazia Volpe, Carla Damiano, Antonietta Tarallo, Giancarlo Parenti, Sandro Banfi, Sabrina Carrella, Alessia Indrieri; miR-181a/b modulation as potential therapeutic approach for AMD treatment. Invest. Ophthalmol. Vis. Sci. 2023;64(8):2113.

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

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Abstract

Purpose : Aged Macular Degeneration (AMD) is a leading cause of severe vision loss in adults. Many factors are involved in AMD onset and progression and limited cures are available to date. We propose to devise a therapeutic strategy that can be applied to a vast number of patients independently of the causative factors. We identified two microRNAs, the miR-181a and b (miR-181a/b), able to control many fundamental cellular processes, and whose inhibition protect ocular cells from damage and rescue vision defects in different models of retinal degenerations. Our goal is to test the efficacy of miR-181a/b inhibition in AMD animal models and pave the way for the set-up of a novel therapy for this complex disease.

Methods : The effect of miR-181a/b inactivation was assessed in 5- and 9-months old Abca4KO and Abca4KO/miR-181a/bKO mice by looking at the accumulation of lipofuscin (by TEM and autofluorescence analysis), at lipid peroxidation (by Malondialdehyde level analysis), and at photoreceptors (PRs) death (by TUNEL assay and cones analysis). Moreover, Abca4KO and Sod1KO mice were subretinally injected with 1x1010 genome copies of Adeno Associated Viruses (AAV) 2/8 encoding a miR-181a/b “sponge” in one eye, and AAV2/8-GFP in the contralateral eye as control. Phenotypic analysis was performed as described above. Electroretinogram (ERG) was performed to assess visual function in 7- 9- and 12-months old Sod1KO mice.

Results : miR-181a/b genetic inactivation in Abca4KO mice significantly reduce lipofuscin accumulation and ameliorate PRs and RPE phenotypes increasing their survival. To test the translational potential of our approach, we generated AAV vectors encoding a miR-181a/b sponge, which allow long-term effects in vivo. The therapeutic agent is safe and effective in Abca4KO mice reducing lipofuscin accumulation and ameliorating retinal phenotypes. Preliminary data also shows a slight amelioration of ERG response in Sod1KO mice injected with miR-181a/b sponge compared to the controls.

Conclusions : Interestingly our results indicate the potential application of miR-181a/b modulation as a novel therapeutic strategy for AMD providing tools and information necessary for the clinical translation. In the long run, the results generated could lead to the design of an RNA-based therapeutic product that could readily be translated into clinical applications for AMD and other forms of retinal degeneration.

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

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