title: An AAV9 coding for frataxin clearly improved the symptoms and prolonged the life of Friedreich ataxia mouse models.
abstract: 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 × 10(11) v.p. to 6 × 10(9) 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 × 10(11) 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 × 10(11) 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.
authors.affiliation: Centre de Recherche du Centre Hospitalier Universitaire de Québec and Department of Molecular Medecine, Faculty of Medecine, Laval University , Québec, Canada.
authors.forename: Catherine
authors.initials: C
authors.lastname: Gérard
authors.affiliation: Fred N. Eshelman Distinguished Professor of Gene Therapy Vice Chair, Division of Molecular Pharmaceutics, UNC Eshelman School of Pharmacy , Chapel Hill, North Carolina, USA.
authors.forename: Xiao
authors.initials: X
authors.lastname: Xiao
authors.affiliation: Centre de Recherche du Centre Hospitalier Universitaire de Québec and Department of Molecular Medecine, Faculty of Medecine, Laval University , Québec, Canada.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Filali
authors.affiliation: Centre de Recherche du Centre Hospitalier Universitaire de Québec and Department of Molecular Medecine, Faculty of Medecine, Laval University , Québec, Canada.
authors.forename: Zoé
authors.initials: Z
authors.lastname: Coulombe
authors.affiliation: Centre de recherche, Institut universitaire de cardiologie et de pneumologie de Québec , Québec, Canada.
authors.forename: Marie
authors.initials: M
authors.lastname: Arsenault
authors.affiliation: Centre de recherche, Institut universitaire de cardiologie et de pneumologie de Québec , Québec, Canada.
authors.forename: Jacques
authors.initials: J
authors.lastname: Couet
authors.affiliation: Fred N. Eshelman Distinguished Professor of Gene Therapy Vice Chair, Division of Molecular Pharmaceutics, UNC Eshelman School of Pharmacy , Chapel Hill, North Carolina, USA.
authors.forename: Juan
authors.initials: J
authors.lastname: Li
authors.affiliation: Centre de recherche, Institut universitaire de cardiologie et de pneumologie de Québec , Québec, Canada.
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Drolet
authors.affiliation: Centre de Recherche du Centre Hospitalier Universitaire de Québec and Department of Molecular Medecine, Faculty of Medecine, Laval University , Québec, Canada.
authors.forename: Pierre
authors.initials: P
authors.lastname: Chapdelaine
authors.affiliation: Centre de Recherche du Centre Hospitalier Universitaire de Québec and Department of Molecular Medecine, Faculty of Medecine, Laval University , Québec, Canada.
authors.forename: Amina
authors.initials: A
authors.lastname: Chikh
authors.affiliation: Centre de Recherche du Centre Hospitalier Universitaire de Québec and Department of Molecular Medecine, Faculty of Medecine, Laval University , Québec, Canada.
authors.forename: Jacques P
authors.initials: JP
authors.lastname: Tremblay