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 cardiac-specific mouse model of FA cardiomyopathy similar to the human disease, we used a cardiac promoter (αMyhc) 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 αMyhc mice had decreased levels of FXN and activity of the mitochondrial complex II/complex IV respiratory chain. At rest, αMyhc 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, αMyhc 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, αMyhc mice stayed above the midline threefold less than littermate controls (p < 0.02). A one-time intravenous administration of 10¹¹ 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 αMyhc mice exhibited exercise performance on a treadmill indistinguishable from littermate controls (p > 0.07). These αMyhc 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.

中文翻译：

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通过 AAV 介导的基因治疗纠正弗里德赖希共济失调心脏表现的应激小鼠模型。


弗里德赖希共济失调 (FA) 是一种由 frataxin (FXN) 表达缺陷引起的常染色体隐性遗传疾病，其特征是进行性共济失调和肥厚性心肌病。尽管心功能不全是 FA 死亡的最常见原因，但由于神经系统疾病限制了肌肉对氧的需求，心脏病在大部分临床病程中仍然处于亚临床状态。之前的FXN基因敲除小鼠模型表现出与人类 FA 类似的致命性心肌病，但与人类的情况相反，未经治疗的小鼠在 2 个月大时就会濒临死亡，而人类的心脏病通常要到 30 岁才会表现出来。该研究旨在创建一个早期 FA 疾病的小鼠模型，该模型与基因治疗可能最有效的时间相关。为了生成类似于人类疾病的 FA 心肌病的心脏特异性小鼠模型，我们使用心脏启动子 (αMyhc) 驱动 CRE 重组酶心脏特异性切除FXN外显子 4，以生成轻度、心脏特异性 FA 模型，该模型在休息，但表现出应激时的心脏表型。 αMyhc 小鼠心脏的 FXN 水平和线粒体复合物 II/复合物 IV 呼吸链的活性降低。静息时，αMyhc 小鼠通过超声心动图评估射血分数和缩短分数来评估，表现出正常的心脏功能，但当心脏受到多巴酚丁胺化学应激时，与同窝对照小鼠相比，αMyhc 小鼠的应激射血分数降低了 62%（ p < 2 × 10 ^-4 ），与应力相关的缩短分数减少 71% ( p < 10 ^-5 )。 当使用在倾斜跑步机上跑步评估功能性心脏性能时，αMyhc 小鼠在中线以上的停留时间比同窝对照小鼠少三倍（ p < 0.02）。一次性静脉注射 10 ^{11 个}基因组拷贝的 AAVrh.10hFXN（一种表达人FXN 的腺相关病毒 (AAV) 血清型 rh10 基因转移载体）可纠正应激诱导的射血分数和缩短分数表型。接受治疗的 αMyhc 小鼠在跑步机上表现出的运动表现与同窝对照小鼠没有区别 ( p > 0.07)。这些 αMyhc 小鼠提供了一个理想的模型来研究 FA 和 AAV 介导的基因治疗纠正人类 FA 典型的应激诱导心脏表型引起的长期心脏并发症。