Mundel Peter
Goldfinch Bio, 215 First Street, 4th Floor, Cambridge, MA, 02142, USA.
Pflugers Arch. 2017 Aug;469(7-8):1029-1037. doi: 10.1007/s00424-017-2015-x. Epub 2017 Jun 23.
In this review, I describe a 30-year journey in the quest for precision medicines for patients with kidney diseases. In 1987, when I started my reseach career, most scientists studying glomerular disease biology were focused on mesangial cells. The crucial role of the podocyte in many kidney diseases characterized by proteinuria, including focal segmental glomerulosclerosis (FSGS) and diabetic nephropathy, had not yet been recognized. We were not aware of genetic causes or drivers of kidney diseases nor of molecular markers and cell culture systems for mechanistic studies of podocyte biology. Tools for generating podocyte-specific knockout mice did not exist, and the key role of the podocyte actin cytoskeleton in the pathogenesis of proteinuria had not yet been identified. Clinically, treatment options for proteinuric kidney diseases were empiric, non-specific, and restricted to steroids and cyclosporine, without an understanding of their underlying mechanism of action. Since then, we have come a long way: a host of genetic causes for FSGS affecting podocytes has been identified, and with the advent of next generation sequencing approaches, the number of genetic causes continues to increase. Thinking "outside the box," empowered me to turn my attention to podocytes, develop the first differentiated podocyte cell culture system, and pioneer studies on the critical role of the podocyte actin cytoskeleton. Now, with the advent of iPSCs, we can build on these efforts by generating human podocytes and kidney organoids from patient cells, which, in combination with CRISPR-Cas9 gene editing and big data analyses, represent important next generation tools for bringing urgently needed precision medicines to patients with kidney disease. These new directions in kidney research should also increase the feasibility of much needed clinical trials in the kidney space. From Heidelberg to Boston, it has been an amazing scientific adventure. I will close with my thoughts about the path forward in making precision medicines for kidney diseases a reality.
在这篇综述中，我描述了为肾病患者探寻精准药物的30年历程。1987年，当我开始我的研究职业生涯时，大多数研究肾小球疾病生物学的科学家都专注于系膜细胞。足细胞在许多以蛋白尿为特征的肾脏疾病（包括局灶节段性肾小球硬化症（FSGS）和糖尿病肾病）中的关键作用尚未得到认可。我们既不知道肾脏疾病的遗传病因或驱动因素，也不了解用于足细胞生物学机制研究的分子标志物和细胞培养系统。当时不存在生成足细胞特异性敲除小鼠的工具，而且足细胞肌动蛋白细胞骨架在蛋白尿发病机制中的关键作用尚未被发现。临床上，蛋白尿性肾脏疾病的治疗选择是经验性的、非特异性的，仅限于类固醇和环孢素，且不了解其潜在作用机制。从那时起，我们已经取得了长足的进步：已经确定了许多影响足细胞的FSGS的遗传病因，随着下一代测序方法的出现，遗传病因的数量持续增加。跳出框框思考使我将注意力转向足细胞，开发了第一个分化的足细胞细胞培养系统，并开创了关于足细胞肌动蛋白细胞骨架关键作用的研究。现在，随着诱导多能干细胞（iPSCs）的出现，我们可以在此基础上，通过从患者细胞中生成人类足细胞和肾脏类器官，结合CRISPR - Cas9基因编辑和大数据分析，这些代表了为肾病患者带来急需的精准药物的重要下一代工具。肾脏研究的这些新方向也应该会增加肾脏领域急需的临床试验的可行性。从海德堡到波士顿，这是一次令人惊叹的科学冒险。我将以我对实现肾病精准药物未来道路的思考作为结尾。
