美国Denali Therapeutics公司Gilbert Di Paolo、Sarah L. DeVos等研究人员合作开发出治疗Grn功能丧失疾病的新方法。相关论文于2021年8月26日在线发表在《细胞》杂志上。

研究人员发现Grn^-/-小鼠表现出双（单酰甘油）磷酸酯（BMP）的全面缺乏，这是一种内吞溶酶体磷脂，研究人员发现它是一种pH值依赖的颗粒蛋白前体（PGRN）相互作用蛋白，也是一种对溶酶体蛋白分解和脂肪分解的氧化还原敏感增强因子。Grn^-/-大脑还显示出葡萄糖脑苷脂酶底物葡萄糖脑苷脂的年龄依赖性二次储存。研究人员开发了一种蛋白质替代策略，即通过设计蛋白质运输工具（PTV）:PGRN——一种重组蛋白质，将PGRN与修改过的Fc结构域连接起来，与人类转铁蛋白受体结合，从而加强中枢神经系统的生物分布。

PTV:PGRN挽救了原代小鼠巨噬细胞和人类iPSC衍生小胶质细胞的各种Grn^-/-表型，包括氧化压力、溶酶体功能障碍和内膜损伤。外周给药的PGV:PGRN纠正了BMP、葡糖鞘氨醇的水平和Grn^-/-中枢神经系统的疾病病理，包括小胶质细胞增多症、脂褐斑和神经元损伤。因此，PTV:PGRN是额颞叶痴呆（GRN-FTD）的潜在生物治疗方法。

据悉，GRN突变导致GRN-FTD，原因是缺乏PGRN，这是一种溶酶体的和分泌的蛋白，其功能不明确。

附：英文原文

Title: Rescue of a lysosomal storage disorder caused by Grn loss of function with a brain penetrant progranulin biologic

Author: Todd Logan, Matthew J. Simon, Anil Rana, Gerald M. Cherf, Ankita Srivastava, Sonnet S. Davis, Ray Lieh Yoon Low, Chi-Lu Chiu, Meng Fang, Fen Huang, Akhil Bhalla, Ceyda Llapashtica, Rachel Prorok, Michelle E. Pizzo, Meredith E.K. Calvert, Elizabeth W. Sun, Jennifer Hsiao-Nakamoto, Yashas Rajendra, Katrina W. Lexa, Devendra B. Srivastava, Bettina van Lengerich, Junhua Wang, Yaneth Robles-Colmenares, Do Jin Kim, Joseph Duque, Melina Lenser, Timothy K. Earr, Hoang Nguyen, Roni Chau, Buyankhishig Tsogtbaatar, Ritesh Ravi, Lukas L. Skuja, Hilda Solanoy, Howard J. Rosen, Bradley F. Boeve, Adam L. Boxer, Hilary W. Heuer, Mark S. Dennis, Mihalis S. Kariolis, Kathryn M. Monroe, Laralynne Przybyla, Pascal E. Sanchez, Rene Meisner, Dolores Diaz, Kirk R. Henne, Ryan J. Watts, Anastasia G. Henry, Kannan Gunasekaran, Giuseppe Astarita, Jung H. Suh, Joseph W. Lewcock, Sarah L. DeVos, Gilbert Di Paolo

Issue&Volume: 2021-08-26

Abstract: GRN mutations cause frontotemporal dementia (GRN-FTD) due to deficiency in progranulin (PGRN), a lysosomal and secreted protein withunclear function. Here, we found that Grn–/– mice exhibit a global deficiency in bis(monoacylglycero)phosphate (BMP), an endolysosomalphospholipid we identified as a pH-dependent PGRN interactor as well as a redox-sensitiveenhancer of lysosomal proteolysis and lipolysis. Grn–/– brains also showed an age-dependent, secondary storage of glucocerebrosidase substrateglucosylsphingosine. We investigated a protein replacement strategy by engineeringprotein transport vehicle (PTV):PGRN—a recombinant protein linking PGRN to a modifiedFc domain that binds human transferrin receptor for enhanced CNS biodistribution.PTV:PGRN rescued various Grn–/– phenotypes in primary murine macrophages and human iPSC-derived microglia, includingoxidative stress, lysosomal dysfunction, and endomembrane damage. Peripherally deliveredPTV:PGRN corrected levels of BMP, glucosylsphingosine, and disease pathology in Grn–/– CNS, including microgliosis, lipofuscinosis, and neuronal damage. PTV:PGRN thus representsa potential biotherapeutic for GRN-FTD.

DOI: 10.1016/j.cell.2021.08.002

Source: https://www.cell.com/cell/fulltext/S0092-8674(21)00944-2