Friedreich’s ataxia (FRDA), a common inherited ataxia, affects the nervous system and the heart, causing cardiomyopathy. The disease is associated with a reduced expression of the mitochondrial protein frataxin (FXN), and adeno-associated viral vector (AAV)-mediated gene transfer can be a potential therapeutic approach to induce frataxin expression. While this approach has been effective in cardiac mouse models of the disease, overexpression of frataxin can cause toxicity. A new study shows that using a low-strength phosphoglycerate kinase (PGK) promotor to express human or mouse frataxin at physiological level in mice reduces toxicity. AAV treatment in frataxin-knockout mice (FXN-KO) prolonged their lives and improved cardiac function compared to vehicle treatment. AAV-treated FXN-KO animals showed a broad distribution of frataxin expression in the cardiac tissue, at very similar levels to wild-type individuals, with no signs of toxicity. By showing that AAV gene therapy with a lower dosage provides benefits while preventing toxicity, these data support an AAV-based approach to treat FRDA-associated cardiomyopathy.

Original reference: Chang, J.C. et al. Mol. Ther. Methods Clin. Dev. 32, 101193 (2024)

弗里德赖希共济失调 (FRDA) 是一种常见的遗传性共济失调，会影响神经系统和心脏，导致心肌病。该疾病与线粒体蛋白 frataxin (FXN) 表达减少有关，腺相关病毒载体 (AAV) 介导的基因转移可能是诱导 frataxin 表达的潜在治疗方法。虽然这种方法在该疾病的心脏小鼠模型中有效，但 frataxin 的过度表达可能会引起毒性。一项新的研究表明，使用低强度磷酸甘油酸激酶 (PGK) 启动子在小鼠体内以生理水平表达人类或小鼠 frataxin 可降低毒性。与媒介物治疗相比，AAV 治疗 frataxin 敲除小鼠 (FXN-KO) 延长了它们的寿命并改善了心脏功能。 AAV 处理的 FXN-KO 动物在心脏组织中表现出广泛的 frataxin 表达分布，其水平与野生型个体非常相似，并且没有毒性迹象。通过表明较低剂量的 AAV 基因治疗在预防毒性的同时提供益处，这些数据支持基于 AAV 的方法来治疗 FRDA 相关心肌病。

原始参考： Chang, JC et al.摩尔。瑟尔。方法临床。开发人员。32、101193 (2024)