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AAV2/8 anti-angiogenic gene therapy using single-chain antibodies inhibits murine choroidal neovascularization

AAV2/8 anti-angiogenic gene therapy using single-chain antibodies inhibits murine choroidal neovascularization
AAV2/8 anti-angiogenic gene therapy using single-chain antibodies inhibits murine choroidal neovascularization
While anti-angiogenic therapies for wet age-related macular degeneration (AMD) are effective for many patients, they require multiple injections, are expensive and prone to complications. Gene therapy could be an elegant solution for this problem by providing a long-term source of anti-angiogenic proteins after a single administration. Another potential issue with current therapeutic proteins containing a fragment crystallizable (Fc) domain (such as whole antibodies like bevacizumab) is the induction of an unwanted immune response. In wet AMD a low level of inflammation is already present, so to avoid exacerbation of disease by the therapeutic protein, we propose single-chain fragment variable antibodies (scFv, which lack the Fc domain) as a safer alternative. To investigate the feasibility of this, anti-vascular endothelial growth factor (VEGF) blocking antibodies in two formats were produced and tested in vitro and in vivo. The scFv transgene was then cloned into an adeno-associated virus (AAV) vector.A therapeutic effect in a mouse model of choroidal neovascularization (CNV) was demonstrated with antibodies in both scFv and immunoglobulin G1 (IgG1) formats (p<0.04). Importantly, the scFv anti-VEGF antibody expressed from an AAV vector also had a significant beneficial effect (p=0.02), providing valuable preclinical data for future translation to the clinic.
2329-0501
86-98
Hughes, Christopher P
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O'Flynn, Neil MJ
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Gatherer, Maureen
bd7b1066-00cd-4673-82fd-2cec00f1ffc0
McClements, Michelle E
c07e03f0-60d6-44a9-b0b0-637e410b8256
Scott, Jennifer
bdc803de-3082-4727-a4ca-f5a1cf3fcfcc
MacLaren, Robert E.
c7a2f458-a7b1-4b96-b88e-d376c90ec059
Goverdhan, Srinivas V
9ae32d5a-5c82-48a4-962d-1ed8acc3991e
Glennie, Martin
9f6f0eff-4560-48c2-80cd-0ec116110ded
Lotery, Andrew
5ecc2d2d-d0b4-468f-ad2c-df7156f8e514
Hughes, Christopher P
a1169e2e-c77e-481d-9588-44f975d4d247
O'Flynn, Neil MJ
a332c6d1-dd58-4c78-b1be-3e7b06d7c358
Gatherer, Maureen
bd7b1066-00cd-4673-82fd-2cec00f1ffc0
McClements, Michelle E
c07e03f0-60d6-44a9-b0b0-637e410b8256
Scott, Jennifer
bdc803de-3082-4727-a4ca-f5a1cf3fcfcc
MacLaren, Robert E.
c7a2f458-a7b1-4b96-b88e-d376c90ec059
Goverdhan, Srinivas V
9ae32d5a-5c82-48a4-962d-1ed8acc3991e
Glennie, Martin
9f6f0eff-4560-48c2-80cd-0ec116110ded
Lotery, Andrew
5ecc2d2d-d0b4-468f-ad2c-df7156f8e514

Hughes, Christopher P, O'Flynn, Neil MJ, Gatherer, Maureen, McClements, Michelle E, Scott, Jennifer, MacLaren, Robert E., Goverdhan, Srinivas V, Glennie, Martin and Lotery, Andrew (2019) AAV2/8 anti-angiogenic gene therapy using single-chain antibodies inhibits murine choroidal neovascularization. Molecular Therapy: Methods & Clinical Development, 13, 86-98. (doi:10.1016/j.omtm.2018.11.005).

Record type: Article

Abstract

While anti-angiogenic therapies for wet age-related macular degeneration (AMD) are effective for many patients, they require multiple injections, are expensive and prone to complications. Gene therapy could be an elegant solution for this problem by providing a long-term source of anti-angiogenic proteins after a single administration. Another potential issue with current therapeutic proteins containing a fragment crystallizable (Fc) domain (such as whole antibodies like bevacizumab) is the induction of an unwanted immune response. In wet AMD a low level of inflammation is already present, so to avoid exacerbation of disease by the therapeutic protein, we propose single-chain fragment variable antibodies (scFv, which lack the Fc domain) as a safer alternative. To investigate the feasibility of this, anti-vascular endothelial growth factor (VEGF) blocking antibodies in two formats were produced and tested in vitro and in vivo. The scFv transgene was then cloned into an adeno-associated virus (AAV) vector.A therapeutic effect in a mouse model of choroidal neovascularization (CNV) was demonstrated with antibodies in both scFv and immunoglobulin G1 (IgG1) formats (p<0.04). Importantly, the scFv anti-VEGF antibody expressed from an AAV vector also had a significant beneficial effect (p=0.02), providing valuable preclinical data for future translation to the clinic.

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More information

Accepted/In Press date: 16 November 2018
e-pub ahead of print date: 22 November 2018
Published date: 14 June 2019

Identifiers

Local EPrints ID: 426731
URI: http://eprints.soton.ac.uk/id/eprint/426731
ISSN: 2329-0501
PURE UUID: 02ddb7a6-04fd-4069-a36a-ee34f3c45340
ORCID for Andrew Lotery: ORCID iD orcid.org/0000-0001-5541-4305

Catalogue record

Date deposited: 11 Dec 2018 17:30
Last modified: 16 Mar 2024 03:32

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Contributors

Author: Christopher P Hughes
Author: Neil MJ O'Flynn
Author: Maureen Gatherer
Author: Michelle E McClements
Author: Jennifer Scott
Author: Robert E. MacLaren
Author: Srinivas V Goverdhan
Author: Martin Glennie
Author: Andrew Lotery ORCID iD

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