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An AAV9 coding for frataxin clearly improved the symptoms and prolonged the life of Friedreich ataxia mouse models.

Gérard C, Xiao X, Filali M, Coulombe Z, Arsenault M, Couet J, Li J, Drolet MC, Chapdelaine P, Chikh A, Tremblay JP - Mol Ther Methods Clin Dev (2014)

Bottom Line: This mutation leads to a reduced expression of frataxin.We have produced an adeno-associated virus (AAV)9 coding for human frataxin (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.

View Article: PubMed Central - PubMed

Affiliation: Centre de Recherche du Centre Hospitalier Universitaire de Québec and Department of Molecular Medecine, Faculty of Medecine, Laval University , Québec, Canada.

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.

No MeSH data available.


Related in: MedlinePlus

Evolution of muscle creatine kinase (MCK)-cre mouse weight. In a, the growth curves of the male mice: L3/L3 mice (n = 26), MCK-cre untreated (no treatment; n = 67) and MCK-cre mice treated with the AAV9-hFXN at 6 × 1011 v.p. (AAV9-hFXN; n = 8) as well as at 6 × 109 v.p. (d1/100; n = 2). In b, the growth curves of the female mice: L3/L3 mice (n = 20), MCK-cre untreated (n = 47) and MCK-cre mice treated with the AAV9-hFXN at 6 × 1011 v.p. (n = 7) as well as at 6 × 109 v.p. (n = 3). There was no difference between the L3/L3 and the different MCK-cre mice groups.
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fig5: Evolution of muscle creatine kinase (MCK)-cre mouse weight. In a, the growth curves of the male mice: L3/L3 mice (n = 26), MCK-cre untreated (no treatment; n = 67) and MCK-cre mice treated with the AAV9-hFXN at 6 × 1011 v.p. (AAV9-hFXN; n = 8) as well as at 6 × 109 v.p. (d1/100; n = 2). In b, the growth curves of the female mice: L3/L3 mice (n = 20), MCK-cre untreated (n = 47) and MCK-cre mice treated with the AAV9-hFXN at 6 × 1011 v.p. (n = 7) as well as at 6 × 109 v.p. (n = 3). There was no difference between the L3/L3 and the different MCK-cre mice groups.

Mentions: The MCK-cre mice followed the same body weight growth curve as the L3/L3 mice. The growth curve of these MCK-cre mice was not modified by the administration of AAV9-hFXN at 6 × 1011 v.p. and 6 × 109 v.p. (d1/100) (Figure 5a,b).


An AAV9 coding for frataxin clearly improved the symptoms and prolonged the life of Friedreich ataxia mouse models.

Gérard C, Xiao X, Filali M, Coulombe Z, Arsenault M, Couet J, Li J, Drolet MC, Chapdelaine P, Chikh A, Tremblay JP - Mol Ther Methods Clin Dev (2014)

Evolution of muscle creatine kinase (MCK)-cre mouse weight. In a, the growth curves of the male mice: L3/L3 mice (n = 26), MCK-cre untreated (no treatment; n = 67) and MCK-cre mice treated with the AAV9-hFXN at 6 × 1011 v.p. (AAV9-hFXN; n = 8) as well as at 6 × 109 v.p. (d1/100; n = 2). In b, the growth curves of the female mice: L3/L3 mice (n = 20), MCK-cre untreated (n = 47) and MCK-cre mice treated with the AAV9-hFXN at 6 × 1011 v.p. (n = 7) as well as at 6 × 109 v.p. (n = 3). There was no difference between the L3/L3 and the different MCK-cre mice groups.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4362356&req=5

fig5: Evolution of muscle creatine kinase (MCK)-cre mouse weight. In a, the growth curves of the male mice: L3/L3 mice (n = 26), MCK-cre untreated (no treatment; n = 67) and MCK-cre mice treated with the AAV9-hFXN at 6 × 1011 v.p. (AAV9-hFXN; n = 8) as well as at 6 × 109 v.p. (d1/100; n = 2). In b, the growth curves of the female mice: L3/L3 mice (n = 20), MCK-cre untreated (n = 47) and MCK-cre mice treated with the AAV9-hFXN at 6 × 1011 v.p. (n = 7) as well as at 6 × 109 v.p. (n = 3). There was no difference between the L3/L3 and the different MCK-cre mice groups.
Mentions: The MCK-cre mice followed the same body weight growth curve as the L3/L3 mice. The growth curve of these MCK-cre mice was not modified by the administration of AAV9-hFXN at 6 × 1011 v.p. and 6 × 109 v.p. (d1/100) (Figure 5a,b).

Bottom Line: This mutation leads to a reduced expression of frataxin.We have produced an adeno-associated virus (AAV)9 coding for human frataxin (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.

View Article: PubMed Central - PubMed

Affiliation: Centre de Recherche du Centre Hospitalier Universitaire de Québec and Department of Molecular Medecine, Faculty of Medecine, Laval University , Québec, Canada.

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.

No MeSH data available.


Related in: MedlinePlus