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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

AAV-hFXN treatment reduced heart hypertrophy in neuron-specific enolase (NSE)-cre mice. The weight of the mouse heart treated or not with the AAV9-hFXN was measured (a) and expressed at sacrifice as a percentage of the whole body weight (b). The groups were composed of L3/L3 (n = 20), NSE-cre treated with AAV9-hFXN at 6 × 1011 v.p. (named AAV9-hFXN; n = 11), at 3 × 1011 v.p. (named d1/2; n = 5), at 6 × 1010 v.p. (named d1/10; n = 4), at 3 × 1010 v.p. (named d1/20; n = 5), at 1.2 × 1010 v.p. (named d1/50; n = 8), at 6 × 109 v.p. (named d1/100; n = 6) and untreated mice (n = 27). The weight of the heart was significantly different from the control L3/L3 and from the untreated mice for the three lowest quantity of virus (*P < 0.05; d1/20, d1/50, and d1/100) (a). The normalized weight was similar to that of L3/L3 for all the treated mice and significantly different (†P ≤ 0.0001) from that of the nontreated NSE-cre mice (b).
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fig4: AAV-hFXN treatment reduced heart hypertrophy in neuron-specific enolase (NSE)-cre mice. The weight of the mouse heart treated or not with the AAV9-hFXN was measured (a) and expressed at sacrifice as a percentage of the whole body weight (b). The groups were composed of L3/L3 (n = 20), NSE-cre treated with AAV9-hFXN at 6 × 1011 v.p. (named AAV9-hFXN; n = 11), at 3 × 1011 v.p. (named d1/2; n = 5), at 6 × 1010 v.p. (named d1/10; n = 4), at 3 × 1010 v.p. (named d1/20; n = 5), at 1.2 × 1010 v.p. (named d1/50; n = 8), at 6 × 109 v.p. (named d1/100; n = 6) and untreated mice (n = 27). The weight of the heart was significantly different from the control L3/L3 and from the untreated mice for the three lowest quantity of virus (*P < 0.05; d1/20, d1/50, and d1/100) (a). The normalized weight was similar to that of L3/L3 for all the treated mice and significantly different (†P ≤ 0.0001) from that of the nontreated NSE-cre mice (b).

Mentions: At the time of sacrifice, the weight of the heart of the mice treated or not with the different doses of AAV9-hFXN was measured (Figure 4a). There was no significant heart weight difference between the L3/L3, the NSE-cre, and the treated NSE-cre mice with 6 × 1011 v.p. to 6 × 1010 v.p. (d1/10). However, because of the difference in body weight, we also expressed the heart weight as a percentage of the total body weight (Figure 4b). This percentage was 0.57 ± 0.11 for L3/L3 mice. The effect of the treatment was strong for all the NSE-cre treated mice, the percentage passing from 1.91 ± 0.61 (not treated) to 0.81 ± 0.23 with the AAV9-hFXN treatment 6 × 1011 v.p. All the treated mice were significantly different from the nontreated mice and not significantly different from the L3/L3 mice.


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)

AAV-hFXN treatment reduced heart hypertrophy in neuron-specific enolase (NSE)-cre mice. The weight of the mouse heart treated or not with the AAV9-hFXN was measured (a) and expressed at sacrifice as a percentage of the whole body weight (b). The groups were composed of L3/L3 (n = 20), NSE-cre treated with AAV9-hFXN at 6 × 1011 v.p. (named AAV9-hFXN; n = 11), at 3 × 1011 v.p. (named d1/2; n = 5), at 6 × 1010 v.p. (named d1/10; n = 4), at 3 × 1010 v.p. (named d1/20; n = 5), at 1.2 × 1010 v.p. (named d1/50; n = 8), at 6 × 109 v.p. (named d1/100; n = 6) and untreated mice (n = 27). The weight of the heart was significantly different from the control L3/L3 and from the untreated mice for the three lowest quantity of virus (*P < 0.05; d1/20, d1/50, and d1/100) (a). The normalized weight was similar to that of L3/L3 for all the treated mice and significantly different (†P ≤ 0.0001) from that of the nontreated NSE-cre mice (b).
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fig4: AAV-hFXN treatment reduced heart hypertrophy in neuron-specific enolase (NSE)-cre mice. The weight of the mouse heart treated or not with the AAV9-hFXN was measured (a) and expressed at sacrifice as a percentage of the whole body weight (b). The groups were composed of L3/L3 (n = 20), NSE-cre treated with AAV9-hFXN at 6 × 1011 v.p. (named AAV9-hFXN; n = 11), at 3 × 1011 v.p. (named d1/2; n = 5), at 6 × 1010 v.p. (named d1/10; n = 4), at 3 × 1010 v.p. (named d1/20; n = 5), at 1.2 × 1010 v.p. (named d1/50; n = 8), at 6 × 109 v.p. (named d1/100; n = 6) and untreated mice (n = 27). The weight of the heart was significantly different from the control L3/L3 and from the untreated mice for the three lowest quantity of virus (*P < 0.05; d1/20, d1/50, and d1/100) (a). The normalized weight was similar to that of L3/L3 for all the treated mice and significantly different (†P ≤ 0.0001) from that of the nontreated NSE-cre mice (b).
Mentions: At the time of sacrifice, the weight of the heart of the mice treated or not with the different doses of AAV9-hFXN was measured (Figure 4a). There was no significant heart weight difference between the L3/L3, the NSE-cre, and the treated NSE-cre mice with 6 × 1011 v.p. to 6 × 1010 v.p. (d1/10). However, because of the difference in body weight, we also expressed the heart weight as a percentage of the total body weight (Figure 4b). This percentage was 0.57 ± 0.11 for L3/L3 mice. The effect of the treatment was strong for all the NSE-cre treated mice, the percentage passing from 1.91 ± 0.61 (not treated) to 0.81 ± 0.23 with the AAV9-hFXN treatment 6 × 1011 v.p. All the treated mice were significantly different from the nontreated mice and not significantly different from the L3/L3 mice.

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