Subretinal AAV delivery of RNAi-therapeutics targeting VEGFA reduces choroidal neovascularization in a large animal model

Silja Hansen Haldrup; Bjørn K. Fabian-Jessing; Thomas Stax Jakobsen; Anna Bøgh Lindholm; Rikke L. Adsersen; Lars Aagaard; Toke Bek; Anne Louise Askou; Thomas J. Corydon

doi:10.1016/j.omtm.2024.101242

Subretinal AAV delivery of RNAi-therapeutics targeting VEGFA reduces choroidal neovascularization in a large animal model

Silja Hansen Haldrup, Bjørn K. Fabian-Jessing, Thomas Stax Jakobsen, Anna Bøgh Lindholm, Rikke L. Adsersen, Lars Aagaard, Toke Bek, Anne Louise Askou, Thomas J. Corydon^*

^*Corresponding author af dette arbejde

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avis › Tidsskriftartikel › Forskning › peer review

4 Citationer (Scopus)

Abstract

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.

Originalsprog	Engelsk
Artikelnummer	101242
Tidsskrift	Molecular Therapy Methods and Clinical Development
Vol/bind	32
Nummer	2
ISSN	2329-0501
DOI	https://doi.org/10.1016/j.omtm.2024.101242
Status	Udgivet - jun. 2024

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10.1016/j.omtm.2024.101242Licens: CC BY-NC-ND

Citationsformater

Haldrup, S. H., Fabian-Jessing, B. K., Jakobsen, T. S., Lindholm, A. B., Adsersen, R. L., Aagaard, L., Bek, T., Askou, A. L., & Corydon, T. J. (2024). Subretinal AAV delivery of RNAi-therapeutics targeting VEGFA reduces choroidal neovascularization in a large animal model. Molecular Therapy Methods and Clinical Development, 32(2), Artikel 101242. https://doi.org/10.1016/j.omtm.2024.101242

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title = "Subretinal AAV delivery of RNAi-therapeutics targeting VEGFA reduces choroidal neovascularization in a large animal model",

abstract = "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.",

keywords = "AAV, AMD, anti-VEGF, CNV, large animal model, miR-agshRNA, pig, retinal gene therapy, RNAi therapeutics",

author = "Haldrup, {Silja Hansen} and Fabian-Jessing, {Bj{\o}rn K.} and Jakobsen, {Thomas Stax} and Lindholm, {Anna B{\o}gh} and Adsersen, {Rikke L.} and Lars Aagaard and Toke Bek and Askou, {Anne Louise} and Corydon, {Thomas J.}",

note = "Publisher Copyright: {\textcopyright} 2024 The Author(s)",

year = "2024",

month = jun,

doi = "10.1016/j.omtm.2024.101242",

language = "English",

volume = "32",

journal = "Molecular Therapy Methods and Clinical Development",

issn = "2329-0501",

publisher = "Cell Press",

number = "2",

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Subretinal AAV delivery of RNAi-therapeutics targeting VEGFA reduces choroidal neovascularization in a large animal model. / Haldrup, Silja Hansen; Fabian-Jessing, Bjørn K.; Jakobsen, Thomas Stax et al.
I: Molecular Therapy Methods and Clinical Development, Bind 32, Nr. 2, 101242, 06.2024.

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avis › Tidsskriftartikel › Forskning › peer review

TY - JOUR

T1 - Subretinal AAV delivery of RNAi-therapeutics targeting VEGFA reduces choroidal neovascularization in a large animal model

AU - Haldrup, Silja Hansen

AU - Fabian-Jessing, Bjørn K.

AU - Jakobsen, Thomas Stax

AU - Lindholm, Anna Bøgh

AU - Adsersen, Rikke L.

AU - Aagaard, Lars

AU - Bek, Toke

AU - Askou, Anne Louise

AU - Corydon, Thomas J.

PY - 2024/6

Y1 - 2024/6

N2 - 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.

AB - 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.

KW - AAV

KW - AMD

KW - anti-VEGF

KW - CNV

KW - large animal model

KW - miR-agshRNA

KW - pig

KW - retinal gene therapy

KW - RNAi therapeutics

U2 - 10.1016/j.omtm.2024.101242

DO - 10.1016/j.omtm.2024.101242

M3 - Journal article

C2 - 38605811

AN - SCOPUS:85189473276

SN - 2329-0501

VL - 32

JO - Molecular Therapy Methods and Clinical Development

JF - Molecular Therapy Methods and Clinical Development

IS - 2

M1 - 101242

ER -

Subretinal AAV delivery of RNAi-therapeutics targeting VEGFA reduces choroidal neovascularization in a large animal model

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