Aleo Serena J, Del Dotto Valentina, Fogazza Mario, Maresca Alessandra, Lodi Tiziana, Goffrini Paola, Ghelli Anna, Rugolo Michela, Carelli Valerio, Baruffini Enrico, Zanna Claudia
Department of Pharmacy and Biotechnology (FABIT), University of Bologna, Bologna 40126, Italy.
Unit of Neurology, Department of Biomedical and NeuroMotor Sciences (DIBINEM), University of Bologna, Bologna 40139, Italy.
Hum Mol Genet. 2021 Jan 21;29(22):3631-3645. doi: 10.1093/hmg/ddaa244.
OPA1 mutations are the major cause of dominant optic atrophy (DOA) and the syndromic form DOA plus, pathologies for which there is no established cure. We used a 'drug repurposing' approach to identify FDA-approved molecules able to rescue the mitochondrial dysfunctions induced by OPA1 mutations. We screened two different chemical libraries by using two yeast strains carrying the mgm1I322M and the chim3P646L mutations, identifying 26 drugs able to rescue their oxidative growth phenotype. Six of them, able to reduce the mitochondrial DNA instability in yeast, have been then tested in Opa1 deleted mouse embryonic fibroblasts expressing the human OPA1 isoform 1 bearing the R445H and D603H mutations. Some of these molecules were able to ameliorate the energetic functions and/or the mitochondrial network morphology, depending on the type of OPA1 mutation. The final validation has been performed in patients' fibroblasts, allowing to select the most effective molecules. Our current results are instrumental to rapidly translating the findings of this drug repurposing approach into clinical trial for DOA and other neurodegenerations caused by OPA1 mutations.
OPA1 突变是显性遗传性视神经萎缩（DOA）及其综合征形式 DOA plus 的主要病因，而这些病症目前尚无治愈方法。我们采用了“药物重新利用”方法，以鉴定能够挽救由 OPA1 突变引起的线粒体功能障碍的 FDA 批准分子。我们使用携带 mgm1I322M 和 chim3P646L 突变的两种酵母菌株筛选了两个不同的化学文库，鉴定出 26 种能够挽救其氧化生长表型的药物。其中六种能够降低酵母中线粒体 DNA 不稳定性的药物，随后在表达携带 R445H 和 D603H 突变的人 OPA1 同工型 1 的 Opa1 缺失小鼠胚胎成纤维细胞中进行了测试。根据 OPA1 突变的类型，其中一些分子能够改善能量功能和/或线粒体网络形态。最终验证在患者成纤维细胞中进行，从而筛选出最有效的分子。我们目前的结果有助于将这种药物重新利用方法的研究结果迅速转化为针对 DOA 和其他由 OPA1 突变引起的神经退行性疾病的临床试验。
