Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Departamento de Biología Molecular, Universidad Autónoma de Madrid, Nicolás Cabrera 1, 28049 Madrid, Spain.
Department of Physiology, Anatomy and Genetics, Sherrington Building, Parks Road, University of Oxford, Oxford OX1 3PT, UK.
Int J Mol Sci. 2021 Feb 11;22(4):1815. doi: 10.3390/ijms22041815.
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.
弗里德里希共济失调是一种常染色体隐性遗传神经退行性疾病，主要与脊髓萎缩和小脑进行性神经退行性变有关。该疾病是由 FXN 基因第一内含子中的 GAA 扩展引起的，导致弗赖赖希共济失调蛋白水平降低，从而导致线粒体功能障碍。目前，尚无有效的治疗方法来延缓弗里德里希共济失调的神经退行性变。一种合理的治疗方法是基因治疗。事实上，已经用编码 FXN 或神经营养因子（如脑源性神经营养因子）的病毒载体治疗弗里德里希共济失调小鼠模型，显示出有希望的结果。因此，基因治疗越来越被认为是最有前途的治疗方法之一。然而，需要克服几个障碍，包括免疫毒性和表型毒性。我们综述了弗里德里希共济失调基因治疗的最新进展，讨论了主要挑战及其最可行的解决方案。
