Zimmerman Brandon, Dakin Leslie A, Fortier Anne, Nanou Evanthia, Blasio Angelo, Mann James, Miller Howard, Fletcher Marissa, Wang Tiansheng, Nanthakumar Suganthini, McCarthy Gizelle, Matar Caline, Matsye Prachi, Wang Guanyu, Snyder Phillip, Daniel Kevin, Swamy Harsha, Sullivan Kelly, Bright Franklin, Powers Audrey, Gagnon Kevin J, Lu Fan, Paula Steven, Khare-Pandit Suvarna, Henry Larry, Hamel Martine, Denis Francois, Nicolas Olivier, Hariparsad Niresh, Kumar Shyamesh, Proctor Jennifer, Senter Timothy, Furey Brinley, Bunnage Mark E
Vertex Pharmaceuticals Incorporated, Boston, MA, USA.
Nat Commun. 2025 Jan 2;16(1):167. doi: 10.1038/s41467-024-55408-2.
Chronic kidney disease affects ~10% of people worldwide and there are no disease modifying therapeutics that address the underlying cause of any form of kidney disease. Genome wide association studies have identified the G1 and G2 variants in the apolipoprotein L1 (APOL1) gene as major contributors to a subtype of proteinuric kidney disease now referred to as APOL1-mediated kidney disease (AMKD). We hypothesized that inhibition of APOL1 could have therapeutic potential for this genetically-defined form of kidney disease. Here we describe the development of preclinical assays and the discovery of potent and specific APOL1 inhibitors with drug-like properties. We provide evidence that APOL1 channel activity drives podocyte injury and that inhibition of this activity stops APOL1-mediated cell death and kidney damage in a transgenic mouse model. These preclinical data, combined with clinical data from our previously published phase 2 proof-of-concept study, support the potential of APOL1 channel inhibition for the treatment of AMKD.
慢性肾脏病影响着全球约10%的人口，目前尚无针对任何形式肾脏疾病根本病因的疾病改善疗法。全基因组关联研究已确定载脂蛋白L1（APOL1）基因中的G1和G2变体是现在称为APOL1介导的肾脏疾病（AMKD）的蛋白尿性肾脏疾病亚型的主要促成因素。我们假设抑制APOL1可能对这种基因定义的肾脏疾病具有治疗潜力。在此，我们描述了临床前检测方法的开发以及具有类药物特性的强效和特异性APOL1抑制剂的发现。我们提供的证据表明，APOL1通道活性会导致足细胞损伤，而抑制这种活性可在转基因小鼠模型中阻止APOL1介导的细胞死亡和肾脏损伤。这些临床前数据，结合我们之前发表的2期概念验证研究的临床数据，支持了抑制APOL1通道治疗AMKD的潜力。
