Prevention and reversal of severe mitochondrial cardiomyopathy by gene therapy in a mouse model of Friedreich's ataxia

2014 ◽  
Vol 20 (5) ◽  
pp. 542-547 ◽  
Author(s):  
Morgane Perdomini ◽  
Brahim Belbellaa ◽  
Laurent Monassier ◽  
Laurence Reutenauer ◽  
Nadia Messaddeq ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Mouse Model ◽  
Friedreich’S Ataxia ◽  
Friedreich's Ataxia ◽  
Mitochondrial Cardiomyopathy

Stress-Induced Mouse Model of the Cardiac Manifestations of Friedreich's Ataxia Corrected by AAV-mediated Gene Therapy

2020 ◽  
Vol 31 (15-16) ◽  
pp. 819-827 ◽  
Author(s):  
Christiana O. Salami ◽  
Katie Jackson ◽  
Clarisse Jose ◽  
Laith Alyass ◽  
Georges-Ibrahim Cisse ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Mouse Model ◽  
Friedreich’S Ataxia ◽  
Friedreich's Ataxia ◽  
Cardiac Manifestations

scholarly journals Future Prospects of Gene Therapy for Friedreich’s Ataxia

2021 ◽  
Vol 22 (4) ◽  
pp. 1815 ◽  
Author(s):  
Gabriel Ocana-Santero ◽  
Javier Díaz-Nido ◽  
Saúl Herranz-Martín
Keyword(s):  
Gene Therapy ◽  
Viral Vectors ◽  
Autosomal Recessive ◽  
State Of The Art ◽  
Friedreich’S Ataxia ◽  
Friedreich's Ataxia ◽  
First Intron ◽  
Progressive Neurodegeneration ◽  
Feasible Solutions ◽  
Neurogenetic Disease

Friedreich’s ataxia is an autosomal recessive neurogenetic disease that is mainly associated with atrophy of the spinal cord and progressive neurodegeneration in the cerebellum. The disease is caused by a GAA-expansion in the first intron of the frataxin gene leading to a decreased level of frataxin protein, which results in mitochondrial dysfunction. Currently, there is no effective treatment to delay neurodegeneration in Friedreich’s ataxia. A plausible therapeutic approach is gene therapy. Indeed, Friedreich’s ataxia mouse models have been treated with viral vectors en-coding for either FXN or neurotrophins, such as brain-derived neurotrophic factor showing promising results. Thus, gene therapy is increasingly consolidating as one of the most promising therapies. However, several hurdles have to be overcome, including immunotoxicity and pheno-toxicity. We review the state of the art of gene therapy in Friedreich’s ataxia, addressing the main challenges and the most feasible solutions for them.

scholarly journals Two New Pimelic Diphenylamide HDAC Inhibitors Induce Sustained Frataxin Upregulation in Cells from Friedreich's Ataxia Patients and in a Mouse Model

PLoS ONE ◽  
2010 ◽  
Vol 5 (1) ◽  
pp. e8825 ◽  
Author(s):  
Myriam Rai ◽  
Elisabetta Soragni ◽  
C. James Chou ◽  
Glenn Barnes ◽  
Steve Jones ◽  
...  
Keyword(s):  
Mouse Model ◽  
Hdac Inhibitors ◽  
Friedreich’S Ataxia ◽  
Friedreich's Ataxia ◽  
In Cells

scholarly journals A TAT–Frataxin fusion protein increases lifespan and cardiac function in a conditional Friedreich's ataxia mouse model

2011 ◽  
Vol 21 (6) ◽  
pp. 1230-1247 ◽  
Author(s):  
Piyush M. Vyas ◽  
Wendy J. Tomamichel ◽  
P. Melanie Pride ◽  
Clifford M. Babbey ◽  
Qiujuan Wang ◽  
...  
Keyword(s):  
Mouse Model ◽  
Fusion Protein ◽  
Cardiac Function ◽  
Friedreich’S Ataxia ◽  
Friedreich's Ataxia

scholarly journals Cytokine therapy-mediated neuroprotection in a Friedreich's ataxia mouse model

2017 ◽  
Vol 81 (2) ◽  
pp. 212-226 ◽  
Author(s):  
Kevin C. Kemp ◽  
Nadia Cerminara ◽  
Kelly Hares ◽  
Juliana Redondo ◽  
Amelia J. Cook ◽  
...  
Keyword(s):  
Mouse Model ◽  
Friedreich’S Ataxia ◽  
Friedreich's Ataxia ◽  
Cytokine Therapy

scholarly journals Frataxin Deficiency Leads to Defects in Expression of Antioxidants and Nrf2 Expression in Dorsal Root Ganglia of the Friedreich's Ataxia YG8R Mouse Model

2013 ◽  
Vol 19 (13) ◽  
pp. 1481-1493 ◽  
Author(s):  
Yuxi Shan ◽  
Robert A. Schoenfeld ◽  
Genki Hayashi ◽  
Eleonora Napoli ◽  
Tasuku Akiyama ◽  
...  
Keyword(s):  
Mouse Model ◽  
Dorsal Root Ganglia ◽  
Dorsal Root ◽  
Friedreich’S Ataxia ◽  
Friedreich's Ataxia ◽  
Nrf2 Expression

scholarly journals Inducible and reversible phenotypes in a novel mouse model of Friedreich’s Ataxia

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Vijayendran Chandran ◽  
Kun Gao ◽  
Vivek Swarup ◽  
Revital Versano ◽  
Hongmei Dong ◽  
...  
Keyword(s):  
Mouse Model ◽  
Recovery Of Function ◽  
Friedreich’S Ataxia ◽  
Multiple Organ ◽  
Friedreich's Ataxia ◽  
Motor Dysfunction ◽  
Relative Contribution ◽  
Adult Mice ◽  
Organ Systems ◽  
Cellular Dysfunction

Friedreich's ataxia (FRDA), the most common inherited ataxia, is caused by recessive mutations that reduce the levels of frataxin (FXN), a mitochondrial iron binding protein. We developed an inducible mouse model of Fxn deficiency that enabled us to control the onset and progression of disease phenotypes by the modulation of Fxn levels. Systemic knockdown of Fxn in adult mice led to multiple phenotypes paralleling those observed in human patients across multiple organ systems. By reversing knockdown after clinical features appear, we were able to determine to what extent observed phenotypes represent reversible cellular dysfunction. Remarkably, upon restoration of near wild-type FXN levels, we observed significant recovery of function, associated pathology and transcriptomic dysregulation even after substantial motor dysfunction and pathology were observed. This model will be of broad utility in therapeutic development and in refining our understanding of the relative contribution of reversible cellular dysfunction at different stages in disease.

scholarly journals Neurobehavioral deficits in the KIKO mouse model of Friedreich’s ataxia

2017 ◽  
Vol 316 ◽  
pp. 183-188 ◽  
Author(s):  
Marissa Z. McMackin ◽  
Chelsea K. Henderson ◽  
Gino A. Cortopassi
Keyword(s):  
Mouse Model ◽  
Friedreich’S Ataxia ◽  
Friedreich's Ataxia ◽  
Neurobehavioral Deficits

scholarly journals Inducible and reversible phenotypes in a novel mouse model of Friedreich’s Ataxia

2017 ◽  
Author(s):  
Vijayendran Chandran ◽  
Kun Gao ◽  
Vivek Swarup ◽  
Revital Versano ◽  
Hongmei Dong ◽  
...  
Keyword(s):  
Mouse Model ◽  
Recovery Of Function ◽  
Friedreich’S Ataxia ◽  
Multiple Organ ◽  
Friedreich's Ataxia ◽  
Motor Dysfunction ◽  
Relative Contribution ◽  
Adult Mice ◽  
Organ Systems ◽  
Cellular Dysfunction

ABSTRACTFriedreich’s ataxia (FRDA), the most common inherited ataxia, is caused by recessive mutations that reduce the levels of frataxin (FXN), a mitochondrial iron binding protein. We developed an inducible mouse model of Fxn deficiency that enabled us to control the onset and progression of disease phenotypes by the modulation of Fxn levels. Systemic knockdown of Fxn in adult mice led to multiple phenotypes paralleling those observed in human patients across multiple organ systems. By reversing knockdown after clinical features appear, we were able to determine to what extent observed phenotypes represent reversible cellular dysfunction. Remarkably, upon restoration of near wild-type FXN levels, we observed significant recovery of function, associated pathology and transcriptomic dysregulation even after substantial motor dysfunction and pathology were observed. This model will be of broad utility in therapeutic development and in refining our understanding of the relative contribution of reversible cellular dysfunction at different stages in disease.

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