Animal Models of Friedreich Ataxia

Pandolfo, Massimo

doi:10.1016/b978-0-12-405195-9.00065-2

Cited by 1 publication

(2 citation statements)

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“…Six other FA murine models have been described (MCK, NSE, PRP, KIKO/KIKI, YG8R/YG22E, and YAC); of these, three (MCK, NSE, and YAC) exhibit a cardiac phenotype. 17,40 The Mck model has a complete deletion of FXN in the heart and skeletal muscle. 41 These mice develop LV hypertrophy, starting at 4 to 5 weeks, with a rapidly associated and progressive geometric remodeling.…”

Section: Cardiac Disease Associated With Famentioning

confidence: 99%

“…9,11,[13][14][15][16] The evaluation of treatment strategies for cardiac manifestations of FA is currently limited to mouse models with severe cardiomyopathy, which are not cardiac specific and do not accurately represent the subclinical manifestations typical of human cardiac disease. 17,18 To study therapies for cardiac manifestations of FA in a mouse model that more accurately reconstitutes the functional characteristics of the human disease, we used the suboptimal Cre-Lox recombination to partially excise FXN exon 4 specifically in the hearts of C57bl/ 6JxCBA mice. As in the human condition, no clinical signs in this model are apparent at rest.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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Friedreich's ataxia (FA), an autosomal recessive disorder caused by a deficiency in the expression of frataxin (FXN), is characterized by progressive ataxia and hypertrophic cardiomyopathy. Although cardiac dysfunction is the most common cause of mortality in FA, the cardiac disease remains subclinical for most of the clinical course because the neurologic disease limits muscle oxygen demands. Previous FXN knockout mouse models exhibit fatal cardiomyopathy similar to human FA, but in contrast to the human condition, untreated mice become moribund by 2 months of age, unlike humans where the cardiac disease often does not manifest until the third decade. The study was designed to create a mouse model for early FA disease relevant to the time for which a gene therapy would likely be most effective. To generate a cardiacspecific mouse model of FA cardiomyopathy similar to the human disease, we used a cardiac promoter (aMyhc) driving CRE recombinase cardiac-specific excision of FXN exon 4 to generate a mild, cardiac-specific FA model that is normal at rest, but exhibits the cardiac phenotype with stress. The hearts of aMyhc mice had decreased levels of FXN and activity of the mitochondrial complex II/complex IV respiratory chain. At rest, aMyhc mice exhibited normal cardiac function as assessed by echocardiographic assessment of ejection fraction and fractional shortening, but when the heart was stressed chemically with dobutamine, aMyhc mice compared with littermate control mice had a 62% reduction in the stress ejection fraction (p < 2 • 10-4) and 71% reduction in stress-related fractional shortening (p < 10-5). When assessing functional cardiac performance using running on an inclined treadmill, aMyhc mice stayed above the midline threefold less than littermate controls (p < 0.02). A one-time intravenous administration of 10 11 genome copies of AAVrh.10hFXN, an adeno-associated virus (AAV) serotype rh10 gene transfer vector expressing human FXN, corrected the stress-induced ejection fraction and fractional shortening phenotypes. Treated aMyhc mice exhibited exercise performance on a treadmill indistinguishable from littermate controls (p > 0.07). These aMyhc mice provide an ideal model to study long-term cardiac complications due to FA and AAV-mediated gene therapy correction of stress-induced cardiac phenotypes typical of human FA.

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Section: Cardiac Disease Associated With Famentioning

confidence: 99%