An AAV9 coding for frataxin clearly improved the symptoms and prolonged the life of Friedreich ataxia mouse models
Friedreich ataxia (FRDA) is a genetic disease due to increased repeats of the GAA trinucleotide in intron 1 of the frataxin gene. This mutation leads to a reduced expression of frataxin. We have produced an adeno-associated virus (AAV)9 coding for human frataxin (AAV9-hFXN). This AAV was delivered b...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2014-01-01
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| Series: | Molecular Therapy: Methods & Clinical Development |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2329050116301127 |
| _version_ | 1819058857748463616 |
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| author | Catherine Gérard Xiao Xiao Mohammed Filali Zoé Coulombe Marie Arsenault Jacques Couet Juan Li Marie-Claude Drolet Pierre Chapdelaine Amina Chikh Jacques P Tremblay |
| author_facet | Catherine Gérard Xiao Xiao Mohammed Filali Zoé Coulombe Marie Arsenault Jacques Couet Juan Li Marie-Claude Drolet Pierre Chapdelaine Amina Chikh Jacques P Tremblay |
| author_sort | Catherine Gérard |
| collection | DOAJ |
| description | Friedreich ataxia (FRDA) is a genetic disease due to increased repeats of the GAA trinucleotide in intron 1 of the frataxin gene. This mutation leads to a reduced expression of frataxin. We have produced an adeno-associated virus (AAV)9 coding for human frataxin (AAV9-hFXN). This AAV was delivered by intraperitoneal (IP) injection to young conditionally knockout mice in which the frataxin gene had been knocked-out in some tissues during embryogenesis by breeding them with mice expressing the Cre recombinase gene under the muscle creatine kinase (MCK) or the neuron-specific enolase (NSE) promoter. In the first part of the study, different doses of virus were tested from 6 × 1011 v.p. to 6 × 109 v.p. in NSE-cre mice and all leading to an increase in life spent of the mice. The higher and the lower dose were also tested in MCK-cre mice. A single administration of the AAV9-hFXN at 6 × 1011 v.p. more than doubled the life of these mice. In fact the MCK-cre mice treated with the AAV9-hFXN were sacrificed for further molecular investigations at the age of 29 weeks without apparent symptoms. Echography analysis of the heart function clearly indicated that the cardiac systolic function was better preserved in the mice that received 6 × 1011 v.p. of AAV9-hFXN. The human frataxin protein was detected by ELISA in the heart, brain, muscles, kidney, and liver with the higher dose of virus in both mouse models. Thus, gene therapy with an AAV9-hFXN is a potential treatment of FRDA. |
| first_indexed | 2024-12-21T14:01:52Z |
| format | Article |
| id | doaj.art-045e7f6aef3643b880e41e531514bf84 |
| institution | Directory Open Access Journal |
| issn | 2329-0501 |
| language | English |
| last_indexed | 2024-12-21T14:01:52Z |
| publishDate | 2014-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Methods & Clinical Development |
| spelling | doaj.art-045e7f6aef3643b880e41e531514bf842022-12-21T19:01:20ZengElsevierMolecular Therapy: Methods & Clinical Development2329-05012014-01-011C10.1038/mtm.2014.44An AAV9 coding for frataxin clearly improved the symptoms and prolonged the life of Friedreich ataxia mouse modelsCatherine Gérard0Xiao Xiao1Mohammed Filali2Zoé Coulombe3Marie Arsenault4Jacques Couet5Juan Li6Marie-Claude Drolet7Pierre Chapdelaine8Amina Chikh9Jacques P Tremblay10Centre de Recherche du Centre Hospitalier Universitaire de Québec and Department of Molecular Medecine, Faculty of Medecine, Laval University, Québec, CanadaFred N. Eshelman Distinguished Professor of Gene Therapy Vice Chair, Division of Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, Chapel Hill, North Carolina, USACentre de Recherche du Centre Hospitalier Universitaire de Québec and Department of Molecular Medecine, Faculty of Medecine, Laval University, Québec, CanadaCentre de Recherche du Centre Hospitalier Universitaire de Québec and Department of Molecular Medecine, Faculty of Medecine, Laval University, Québec, CanadaCentre de recherche, Institut universitaire de cardiologie et de pneumologie de Québec, Québec, CanadaCentre de recherche, Institut universitaire de cardiologie et de pneumologie de Québec, Québec, CanadaFred N. Eshelman Distinguished Professor of Gene Therapy Vice Chair, Division of Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, Chapel Hill, North Carolina, USACentre de recherche, Institut universitaire de cardiologie et de pneumologie de Québec, Québec, CanadaCentre de Recherche du Centre Hospitalier Universitaire de Québec and Department of Molecular Medecine, Faculty of Medecine, Laval University, Québec, CanadaCentre de Recherche du Centre Hospitalier Universitaire de Québec and Department of Molecular Medecine, Faculty of Medecine, Laval University, Québec, CanadaCentre de Recherche du Centre Hospitalier Universitaire de Québec and Department of Molecular Medecine, Faculty of Medecine, Laval University, Québec, CanadaFriedreich ataxia (FRDA) is a genetic disease due to increased repeats of the GAA trinucleotide in intron 1 of the frataxin gene. This mutation leads to a reduced expression of frataxin. We have produced an adeno-associated virus (AAV)9 coding for human frataxin (AAV9-hFXN). This AAV was delivered by intraperitoneal (IP) injection to young conditionally knockout mice in which the frataxin gene had been knocked-out in some tissues during embryogenesis by breeding them with mice expressing the Cre recombinase gene under the muscle creatine kinase (MCK) or the neuron-specific enolase (NSE) promoter. In the first part of the study, different doses of virus were tested from 6 × 1011 v.p. to 6 × 109 v.p. in NSE-cre mice and all leading to an increase in life spent of the mice. The higher and the lower dose were also tested in MCK-cre mice. A single administration of the AAV9-hFXN at 6 × 1011 v.p. more than doubled the life of these mice. In fact the MCK-cre mice treated with the AAV9-hFXN were sacrificed for further molecular investigations at the age of 29 weeks without apparent symptoms. Echography analysis of the heart function clearly indicated that the cardiac systolic function was better preserved in the mice that received 6 × 1011 v.p. of AAV9-hFXN. The human frataxin protein was detected by ELISA in the heart, brain, muscles, kidney, and liver with the higher dose of virus in both mouse models. Thus, gene therapy with an AAV9-hFXN is a potential treatment of FRDA.http://www.sciencedirect.com/science/article/pii/S2329050116301127 |
| spellingShingle | Catherine Gérard Xiao Xiao Mohammed Filali Zoé Coulombe Marie Arsenault Jacques Couet Juan Li Marie-Claude Drolet Pierre Chapdelaine Amina Chikh Jacques P Tremblay An AAV9 coding for frataxin clearly improved the symptoms and prolonged the life of Friedreich ataxia mouse models Molecular Therapy: Methods & Clinical Development |
| title | An AAV9 coding for frataxin clearly improved the symptoms and prolonged the life of Friedreich ataxia mouse models |
| title_full | An AAV9 coding for frataxin clearly improved the symptoms and prolonged the life of Friedreich ataxia mouse models |
| title_fullStr | An AAV9 coding for frataxin clearly improved the symptoms and prolonged the life of Friedreich ataxia mouse models |
| title_full_unstemmed | An AAV9 coding for frataxin clearly improved the symptoms and prolonged the life of Friedreich ataxia mouse models |
| title_short | An AAV9 coding for frataxin clearly improved the symptoms and prolonged the life of Friedreich ataxia mouse models |
| title_sort | aav9 coding for frataxin clearly improved the symptoms and prolonged the life of friedreich ataxia mouse models |
| url | http://www.sciencedirect.com/science/article/pii/S2329050116301127 |
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