利用常见和罕见的基因变异对肌萎缩性侧索硬化症的候选药物进行重新定位。

IF 4.5 Q1 CLINICAL NEUROLOGY
Brain communications Pub Date : 2025-05-09 eCollection Date: 2025-01-01 DOI:10.1093/braincomms/fcaf184
Zachary F Gerring, Oneil G Bhalala, Liam G Fearnley, Lotta E Oikari, Anthony R White, Eske M Derks, Rosie Watson, Nawaf Yassi, Melanie Bahlo, William R Reay
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引用次数: 0

摘要

肌萎缩性侧索硬化症(ALS)是一种毁灭性的神经退行性疾病,迫切需要新的疾病修饰疗法。鉴于药物发现管道中的瓶颈日益增加,重新利用现有药物治疗ALS可能是加快转化和改善疾病结果的途径。然而,肌萎缩侧索硬化症是一种异质性疾病,其病因特征仍然不明确,这使得有效地重新定位药物的努力变得复杂。我们建议,ALS遗传倾向性的多基因结构,范围从超罕见、高影响变异到小个体效应的常见频率位点,可以用来优先考虑更适用于ALS临床人群的药物再利用候选药物。在这里,我们利用常见和罕见频率的ALS遗传风险与一种新的方法来发现治疗类,可能是ALS的前瞻性重新利用的机会。常见的变异主导分析结合了基于位置和功能基因的snp基因型测试,这些测试来自ALS全基因组关联研究,并通过B-Raf抑制剂暗示有丝分裂原激活的蛋白激酶信号相关的下调,作为重新利用的预期靶点。罕见变异导向的方法利用来自全基因组变异关联研究队列子集的全基因组测序数据的外显子变异的罕见变异负担测试,并优先考虑与b族维生素相关的候选者,如钴胺素和烟酸。这些假定的重新利用机会的临床特征揭示了遗传支持现有生物学,相关化合物正在积极地通过ALS临床研究进行。此外,利用来自ALS衍生细胞系的转录组学数据,这些细胞系携带导致家族性ALS的基因(C9orf72、SOD1、FUS和TARDBP)的致病变异,表明B-Raf抑制剂的作用可能与C9orf72携带者特别相关,而b -维生素信号相关靶点的信号在SOD1携带者中最强。总之,我们证明了考虑ALS的常见和罕见变异介导风险的治疗可操作性的重要性,因为这种疾病具有巨大的生物学异质性。未来的临床前和临床研究现在需要进一步表征这些优先化合物的可追溯性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Drug repurposing candidates for amyotrophic lateral sclerosis using common and rare genetic variants.

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative condition for which novel disease modifying therapies are urgently needed. Given the increasing bottlenecks in drug discovery pipelines, repurposing existing drugs for ALS may represent a path to expedite translation and improve disease outcomes. However, ALS is a heterogeneous disease for which the aetiology remains poorly characterized, complicating efforts to effectively repurpose drugs. We propose that the polygenic architecture of ALS genetic liability, which ranges from ultra-rare, high-impact variation to common frequency loci of small-individual effect, could be leveraged to prioritize drug repurposing candidates which are more generalizable to the ALS clinical population. Here, we utilize common and rare frequency ALS genetic risk with a novel approach to uncover therapeutic classes that may be prospective repurposing opportunities in ALS. The common variant-led analyses integrated both positional-based and functional gene-based tests on SNP-genotype data from a genome-wide association study of ALS and implicated mitogen-activated protein kinase signalling related downregulation through B-Raf inhibitors as a prospective target for repurposing. The rare variant-led approaches leveraged rare variant burden testing of exonic variation on whole genome-sequencing data from a subset of the common variant genome-wide association study cohort and prioritized B-vitamin related candidates, such as cobalamin and niacin. Clinical characterization of these putative repurposing opportunities revealed genetic support to existing biology for which related compounds are actively proceeding through ALS clinical studies. Moreover, leveraging transcriptomic data from ALS derived cell lines carrying a selection of pathogenic variants in genes that cause familial forms of ALS (C9orf72, SOD1, FUS and TARDBP) suggested that the action of B-Raf inhibitors may be of particular relevance to C9orf72 carriers, whilst the signal for B-vitamin signalling related targets was strongest in SOD1 carriers. In summary, we demonstrate the importance of considering the therapeutic actionability of both common and rare-variant mediated risk for ALS given the immense biological heterogeneity of this disorder. Future pre-clinical and clinical studies are now warranted to further characterize the tractability of these prioritized compounds.

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