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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.
86-98
Lotery, Andrew
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Hughes, Christopher P
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Gatherer, Maureen
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McClements, Michelle E
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Scott, Jennifer
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MacLaren, Robert E.
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Goverdhan, Srinivas V
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Glennie, Martin J.
7c33c8f5-20b9-45b0-8ced-1243576f2fa0
Lotery, Andrew
5ecc2d2d-d0b4-468f-ad2c-df7156f8e514
Hughes, Christopher P
a1169e2e-c77e-481d-9588-44f975d4d247
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 J.
7c33c8f5-20b9-45b0-8ced-1243576f2fa0

Lotery, Andrew, Hughes, Christopher P, Gatherer, Maureen, McClements, Michelle E, Scott, Jennifer, MacLaren, Robert E., Goverdhan, Srinivas V and Glennie, Martin J. (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: https://eprints.soton.ac.uk/id/eprint/426731
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: 20 Jul 2019 01:01

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