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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

Cage activity. The activity was estimated for the different groups of mice (L3/L3, n = 11; muscle creatine kinase (MCK)-cre, n = 15; MCK-cre treated with 6 × 1011 v.p. of AAV9-hFXN, n = 7; neuron-specific enolase (NSE)-cre, n = 4 and NSE-cre treated with 6 × 1011 v.p. of AAV9-hFXN, n = 5) as the distance traveled in meters (a), the mean rear duration in seconds (b), the duration of immobility in seconds (c), and the number of immobile episodes (d). The injection of AAV9-hFXN significantly improved the distance traveled (a) and the mean rear duration (b) of the NSE-cre treated mice. The *** indicate significant difference at P less than 0.0001. P ≤ 0.05*; P ≤ 0.001**; P ≤ 0.0001***.
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fig8: Cage activity. The activity was estimated for the different groups of mice (L3/L3, n = 11; muscle creatine kinase (MCK)-cre, n = 15; MCK-cre treated with 6 × 1011 v.p. of AAV9-hFXN, n = 7; neuron-specific enolase (NSE)-cre, n = 4 and NSE-cre treated with 6 × 1011 v.p. of AAV9-hFXN, n = 5) as the distance traveled in meters (a), the mean rear duration in seconds (b), the duration of immobility in seconds (c), and the number of immobile episodes (d). The injection of AAV9-hFXN significantly improved the distance traveled (a) and the mean rear duration (b) of the NSE-cre treated mice. The *** indicate significant difference at P less than 0.0001. P ≤ 0.05*; P ≤ 0.001**; P ≤ 0.0001***.

Mentions: The following behavior parameters were analyzed: distance traveled, immobile time, rear duration, and episode immobile (Figure 8a–d). The behavior of the MCK-cre mice was not different from that of L3/L3 mice (Figure 8). On the contrary, the NSE-cre mice were clearly different from the L3/L3 for all these parameters. These mice were less active (Figure 8a,c). However, after the injection with the AAV9-hFXN, the NSE-cre mice (NSE-cre-AAV) got back to normal activities (Figure 8a–d). The NSE-cre treated mice appeared quite normal and were clearly different from the NSE mutants that did not receive the AAV9-FXN treatment.


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)

Cage activity. The activity was estimated for the different groups of mice (L3/L3, n = 11; muscle creatine kinase (MCK)-cre, n = 15; MCK-cre treated with 6 × 1011 v.p. of AAV9-hFXN, n = 7; neuron-specific enolase (NSE)-cre, n = 4 and NSE-cre treated with 6 × 1011 v.p. of AAV9-hFXN, n = 5) as the distance traveled in meters (a), the mean rear duration in seconds (b), the duration of immobility in seconds (c), and the number of immobile episodes (d). The injection of AAV9-hFXN significantly improved the distance traveled (a) and the mean rear duration (b) of the NSE-cre treated mice. The *** indicate significant difference at P less than 0.0001. P ≤ 0.05*; P ≤ 0.001**; P ≤ 0.0001***.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig8: Cage activity. The activity was estimated for the different groups of mice (L3/L3, n = 11; muscle creatine kinase (MCK)-cre, n = 15; MCK-cre treated with 6 × 1011 v.p. of AAV9-hFXN, n = 7; neuron-specific enolase (NSE)-cre, n = 4 and NSE-cre treated with 6 × 1011 v.p. of AAV9-hFXN, n = 5) as the distance traveled in meters (a), the mean rear duration in seconds (b), the duration of immobility in seconds (c), and the number of immobile episodes (d). The injection of AAV9-hFXN significantly improved the distance traveled (a) and the mean rear duration (b) of the NSE-cre treated mice. The *** indicate significant difference at P less than 0.0001. P ≤ 0.05*; P ≤ 0.001**; P ≤ 0.0001***.
Mentions: The following behavior parameters were analyzed: distance traveled, immobile time, rear duration, and episode immobile (Figure 8a–d). The behavior of the MCK-cre mice was not different from that of L3/L3 mice (Figure 8). On the contrary, the NSE-cre mice were clearly different from the L3/L3 for all these parameters. These mice were less active (Figure 8a,c). However, after the injection with the AAV9-hFXN, the NSE-cre mice (NSE-cre-AAV) got back to normal activities (Figure 8a–d). The NSE-cre treated mice appeared quite normal and were clearly different from the NSE mutants that did not receive the AAV9-FXN treatment.

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