Systemic Treatment of Fabry Disease Using a Novel AAV9 Vector Expressing α-Galactosidase A

Fabry disease is a rare X-linked disorder affecting α-galactosidase A, a rate-limiting enzyme in lysosomal catabolism of glycosphingolipids. Current treatments present important limitations, such as low half-life and limited distribution, which gene therapy can overcome. The aim of this work was to...

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Main Authors: Maria Grazia Biferi, Mathilde Cohen-Tannoudji, Andrea García-Silva, Olga Souto-Rodríguez, Irene Viéitez-González, Beatriz San-Millán-Tejado, Andrea Fernández-Carrera, Tania Pérez-Márquez, Susana Teijeira-Bautista, Soraya Barrera, Vanesa Domínguez, Thibaut Marais, África González-Fernández, Martine Barkats, Saida Ortolano
Format: Article
Language:English
Published: Elsevier 2021-03-01
Series:Molecular Therapy: Methods & Clinical Development
Subjects:
Online Access:http://www.sciencedirect.com/science/article/pii/S2329050120302205
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author Maria Grazia Biferi
Mathilde Cohen-Tannoudji
Andrea García-Silva
Olga Souto-Rodríguez
Irene Viéitez-González
Beatriz San-Millán-Tejado
Andrea Fernández-Carrera
Tania Pérez-Márquez
Susana Teijeira-Bautista
Soraya Barrera
Vanesa Domínguez
Thibaut Marais
África González-Fernández
Martine Barkats
Saida Ortolano
spellingShingle Maria Grazia Biferi
Mathilde Cohen-Tannoudji
Andrea García-Silva
Olga Souto-Rodríguez
Irene Viéitez-González
Beatriz San-Millán-Tejado
Andrea Fernández-Carrera
Tania Pérez-Márquez
Susana Teijeira-Bautista
Soraya Barrera
Vanesa Domínguez
Thibaut Marais
África González-Fernández
Martine Barkats
Saida Ortolano
Systemic Treatment of Fabry Disease Using a Novel AAV9 Vector Expressing α-Galactosidase A
Molecular Therapy: Methods & Clinical Development
Fabry disease
lysosomal storage disorders
adeno asociated virus-9
gene therapy
blood brain barrier
gene transfer
author_facet Maria Grazia Biferi
Mathilde Cohen-Tannoudji
Andrea García-Silva
Olga Souto-Rodríguez
Irene Viéitez-González
Beatriz San-Millán-Tejado
Andrea Fernández-Carrera
Tania Pérez-Márquez
Susana Teijeira-Bautista
Soraya Barrera
Vanesa Domínguez
Thibaut Marais
África González-Fernández
Martine Barkats
Saida Ortolano
author_sort Maria Grazia Biferi
title Systemic Treatment of Fabry Disease Using a Novel AAV9 Vector Expressing α-Galactosidase A
title_short Systemic Treatment of Fabry Disease Using a Novel AAV9 Vector Expressing α-Galactosidase A
title_full Systemic Treatment of Fabry Disease Using a Novel AAV9 Vector Expressing α-Galactosidase A
title_fullStr Systemic Treatment of Fabry Disease Using a Novel AAV9 Vector Expressing α-Galactosidase A
title_full_unstemmed Systemic Treatment of Fabry Disease Using a Novel AAV9 Vector Expressing α-Galactosidase A
title_sort systemic treatment of fabry disease using a novel aav9 vector expressing α-galactosidase a
publisher Elsevier
series Molecular Therapy: Methods & Clinical Development
issn 2329-0501
publishDate 2021-03-01
description Fabry disease is a rare X-linked disorder affecting α-galactosidase A, a rate-limiting enzyme in lysosomal catabolism of glycosphingolipids. Current treatments present important limitations, such as low half-life and limited distribution, which gene therapy can overcome. The aim of this work was to test a novel adeno-associated viral vector, serotype 9 (AAV9), ubiquitously expressing human α-galactosidase A to treat Fabry disease (scAAV9-PGK-GLA). The vector was preliminary tested in newborns of a Fabry disease mouse model. 5 months after treatment, α-galactosidase A activity was detectable in the analyzed tissues, including the central nervous system. Moreover, we tested the vector in adult animals of both sexes at two doses and disease stages (presymptomatic and symptomatic) by single intravenous injection. We found that the exogenous α-galactosidase A was active in peripheral tissues as well as the central nervous system and prevented glycosphingolipid accumulation in treated animals up to 5 months following injection. Antibodies against α-galactosidase A were produced in 9 out of 32 treated animals, although enzyme activity in tissues was not significantly affected. These results demonstrate that scAAV9-PGK-GLA can drive widespread and sustained expression of α-galactosidase A, cross the blood brain barrier after systemic delivery, and reduce pathological signs of the Fabry disease mouse model.
topic Fabry disease
lysosomal storage disorders
adeno asociated virus-9
gene therapy
blood brain barrier
gene transfer
url http://www.sciencedirect.com/science/article/pii/S2329050120302205
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spelling doaj-b2d13278a02c48deb45d598f9f6bd1882021-03-13T04:23:33ZengElsevierMolecular Therapy: Methods & Clinical Development2329-05012021-03-0120117Systemic Treatment of Fabry Disease Using a Novel AAV9 Vector Expressing α-Galactosidase AMaria Grazia Biferi0Mathilde Cohen-Tannoudji1Andrea García-Silva2Olga Souto-Rodríguez3Irene Viéitez-González4Beatriz San-Millán-Tejado5Andrea Fernández-Carrera6Tania Pérez-Márquez7Susana Teijeira-Bautista8Soraya Barrera9Vanesa Domínguez10Thibaut Marais11África González-Fernández12Martine Barkats13Saida Ortolano14Sorbonne Université, INSERM, Institute of Myology, Centre of Research in Myology, 75013 Paris, FranceSorbonne Université, INSERM, Institute of Myology, Centre of Research in Myology, 75013 Paris, FranceRare Diseases and Pediatric Medicine Research Group, Galicia Sur Health Research Institute (IIS Galicia Sur), SERGAS-UVIGO, Hospital Álvaro Cunqueiro, 36312 Vigo, SpainRare Diseases and Pediatric Medicine Research Group, Galicia Sur Health Research Institute (IIS Galicia Sur), SERGAS-UVIGO, Hospital Álvaro Cunqueiro, 36312 Vigo, SpainRare Diseases and Pediatric Medicine Research Group, Galicia Sur Health Research Institute (IIS Galicia Sur), SERGAS-UVIGO, Hospital Álvaro Cunqueiro, 36312 Vigo, SpainRare Diseases and Pediatric Medicine Research Group, Galicia Sur Health Research Institute (IIS Galicia Sur), SERGAS-UVIGO, Hospital Álvaro Cunqueiro, 36312 Vigo, SpainRare Diseases and Pediatric Medicine Research Group, Galicia Sur Health Research Institute (IIS Galicia Sur), SERGAS-UVIGO, Hospital Álvaro Cunqueiro, 36312 Vigo, SpainRare Diseases and Pediatric Medicine Research Group, Galicia Sur Health Research Institute (IIS Galicia Sur), SERGAS-UVIGO, Hospital Álvaro Cunqueiro, 36312 Vigo, SpainRare Diseases and Pediatric Medicine Research Group, Galicia Sur Health Research Institute (IIS Galicia Sur), SERGAS-UVIGO, Hospital Álvaro Cunqueiro, 36312 Vigo, SpainRare Diseases and Pediatric Medicine Research Group, Galicia Sur Health Research Institute (IIS Galicia Sur), SERGAS-UVIGO, Hospital Álvaro Cunqueiro, 36312 Vigo, SpainBioexperimentation Service of the University of Vigo (Sbio), Campus Universitario Lagoas, Marcosende, 36310 Vigo, Spain; CINBIO, Centro de Investigaciones Biomédicas, Universidade de Vigo, Immunology Group, Campus Universitario Lagoas, Marcosende, 36310 Vigo, Spain; Immunology Group, Galicia Sur Health Research Institute (IIS Galicia Sur), SERGAS-UVIGO, Vigo, SpainSorbonne Université, INSERM, Institute of Myology, Centre of Research in Myology, 75013 Paris, FranceCINBIO, Centro de Investigaciones Biomédicas, Universidade de Vigo, Immunology Group, Campus Universitario Lagoas, Marcosende, 36310 Vigo, Spain; Immunology Group, Galicia Sur Health Research Institute (IIS Galicia Sur), SERGAS-UVIGO, Vigo, SpainSorbonne Université, INSERM, Institute of Myology, Centre of Research in Myology, 75013 Paris, FranceRare Diseases and Pediatric Medicine Research Group, Galicia Sur Health Research Institute (IIS Galicia Sur), SERGAS-UVIGO, Hospital Álvaro Cunqueiro, 36312 Vigo, Spain; Corresponding author: Saida Ortolano, PhD, Rare Diseases and Pediatric Medicine, Galicia Sur Health Research Institute, Hospital Álvaro Cunqueiro, Bloque Tecnico, Planta 2 A, Estrada Clara Campoamor 341, 36312 Vigo (Pontevedra), Spain.Fabry disease is a rare X-linked disorder affecting α-galactosidase A, a rate-limiting enzyme in lysosomal catabolism of glycosphingolipids. Current treatments present important limitations, such as low half-life and limited distribution, which gene therapy can overcome. The aim of this work was to test a novel adeno-associated viral vector, serotype 9 (AAV9), ubiquitously expressing human α-galactosidase A to treat Fabry disease (scAAV9-PGK-GLA). The vector was preliminary tested in newborns of a Fabry disease mouse model. 5 months after treatment, α-galactosidase A activity was detectable in the analyzed tissues, including the central nervous system. Moreover, we tested the vector in adult animals of both sexes at two doses and disease stages (presymptomatic and symptomatic) by single intravenous injection. We found that the exogenous α-galactosidase A was active in peripheral tissues as well as the central nervous system and prevented glycosphingolipid accumulation in treated animals up to 5 months following injection. Antibodies against α-galactosidase A were produced in 9 out of 32 treated animals, although enzyme activity in tissues was not significantly affected. These results demonstrate that scAAV9-PGK-GLA can drive widespread and sustained expression of α-galactosidase A, cross the blood brain barrier after systemic delivery, and reduce pathological signs of the Fabry disease mouse model.http://www.sciencedirect.com/science/article/pii/S2329050120302205Fabry diseaselysosomal storage disordersadeno asociated virus-9gene therapyblood brain barriergene transfer