Subretinal AAV delivery of RNAi-therapeutics targeting VEGFA reduces choroidal neovascularization in a large animal model
© 2024 The Author(s)..
Neovascular age-related macular degeneration (nAMD) is a frequent cause of vision loss among the elderly in the Western world. Current disease management with repeated injections of anti-VEGF agents accumulates the risk for adverse events and constitutes a burden for society and the individual patient. Sustained suppression of VEGF using gene therapy is an attractive alternative, which we explored using adeno-associated virus (AAV)-based delivery of novel RNA interference (RNAi) effectors in a porcine model of choroidal neovascularization (CNV). The potency of VEGFA-targeting, Ago2-dependent short hairpin RNAs placed in pri-microRNA scaffolds (miR-agshRNA) was established in vitro and in vivo in mice. Subsequently, AAV serotype 8 (AAV2.8) vectors encoding VEGFA-targeting or irrelevant miR-agshRNAs under the control of a tissue-specific promotor were delivered to the porcine retina via subretinal injection before CNV induction by laser. Notably, VEGFA-targeting miR-agshRNAs resulted in a significant and sizable reduction of CNV compared with the non-targeting control. We also demonstrated that single-stranded and self-complementary AAV2.8 vectors efficiently transduce porcine retinal pigment epithelium cells but differ in their transduction characteristics and retinal safety. Collectively, our data demonstrated a robust anti-angiogenic effect of VEGFA-targeting miR-aghsRNAs in a large translational animal model, thereby suggesting AAV-based delivery of anti-VEGFA RNAi therapeutics as a valuable tool for the management of nAMD.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:32 |
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| Enthalten in: |
Molecular therapy. Methods & clinical development - 32(2024), 2 vom: 13. Apr., Seite 101242 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Haldrup, Silja Hansen [VerfasserIn] |
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| Links: |
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| Themen: |
AAV |
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| Anmerkungen: |
Date Revised 25.04.2024 published: Electronic-eCollection Citation Status PubMed-not-MEDLINE |
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| doi: |
10.1016/j.omtm.2024.101242 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM370951298 |
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| 520 | |a © 2024 The Author(s). | ||
| 520 | |a Neovascular age-related macular degeneration (nAMD) is a frequent cause of vision loss among the elderly in the Western world. Current disease management with repeated injections of anti-VEGF agents accumulates the risk for adverse events and constitutes a burden for society and the individual patient. Sustained suppression of VEGF using gene therapy is an attractive alternative, which we explored using adeno-associated virus (AAV)-based delivery of novel RNA interference (RNAi) effectors in a porcine model of choroidal neovascularization (CNV). The potency of VEGFA-targeting, Ago2-dependent short hairpin RNAs placed in pri-microRNA scaffolds (miR-agshRNA) was established in vitro and in vivo in mice. Subsequently, AAV serotype 8 (AAV2.8) vectors encoding VEGFA-targeting or irrelevant miR-agshRNAs under the control of a tissue-specific promotor were delivered to the porcine retina via subretinal injection before CNV induction by laser. Notably, VEGFA-targeting miR-agshRNAs resulted in a significant and sizable reduction of CNV compared with the non-targeting control. We also demonstrated that single-stranded and self-complementary AAV2.8 vectors efficiently transduce porcine retinal pigment epithelium cells but differ in their transduction characteristics and retinal safety. Collectively, our data demonstrated a robust anti-angiogenic effect of VEGFA-targeting miR-aghsRNAs in a large translational animal model, thereby suggesting AAV-based delivery of anti-VEGFA RNAi therapeutics as a valuable tool for the management of nAMD | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a AAV | |
| 650 | 4 | |a AMD | |
| 650 | 4 | |a CNV | |
| 650 | 4 | |a RNAi therapeutics | |
| 650 | 4 | |a anti-VEGF | |
| 650 | 4 | |a large animal model | |
| 650 | 4 | |a miR-agshRNA | |
| 650 | 4 | |a pig | |
| 650 | 4 | |a retinal gene therapy | |
| 700 | 1 | |a Fabian-Jessing, Bjørn K |e verfasserin |4 aut | |
| 700 | 1 | |a Jakobsen, Thomas Stax |e verfasserin |4 aut | |
| 700 | 1 | |a Lindholm, Anna Bøgh |e verfasserin |4 aut | |
| 700 | 1 | |a Adsersen, Rikke L |e verfasserin |4 aut | |
| 700 | 1 | |a Aagaard, Lars |e verfasserin |4 aut | |
| 700 | 1 | |a Bek, Toke |e verfasserin |4 aut | |
| 700 | 1 | |a Askou, Anne Louise |e verfasserin |4 aut | |
| 700 | 1 | |a Corydon, Thomas J |e verfasserin |4 aut | |
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