Frontotemporal dementia (FTD) is a neurodegenerative disease, leading to behavioral changes and language difficulties. Heterozygous loss-of-function mutations in progranulin (GRN) induce haploinsufficiency of the protein and are associated with up to one third of all genetic FTD cases worldwide. While loss of GRN is primarily associated with neurodegeneration, the biological functions of the secreted growth factor-like protein are more diverse, ranging from wound healing, inflammation, vasculogenesis and metabolic regulation to tumor cell growth and metastasis. To date no disease modifying treatments exist for FTD, but different therapeutic approaches to boost GRN levels in the central nervous system are currently being developed (including AAV-mediated GRN gene delivery as well as anti-SORT1 antibody therapy). In this review, we provide an overview of the multifaceted regulation of GRN levels and the corresponding therapeutic avenues. We discuss opportunities, advantages and potential drawbacks of the diverse approaches. Additionally, we highlight the therapeutic potential of elevating GRN levels beyond patients with loss-of-function mutations in GRN.

中文翻译：

---

调整颗粒蛋白前体表达：治疗途径和机会

额颞叶痴呆 (FTD) 是一种神经退行性疾病，会导致行为改变和语言障碍。颗粒蛋白前体 (GRN) 中的杂合功能丧失突变会导致该蛋白质的单倍剂量不足，并且与全球所有 FTD 遗传病例的三分之一有关。虽然 GRN 的丧失主要与神经变性有关，但分泌的生长因子样蛋白的生物学功能更加多样化，从伤口愈合、炎症、血管生成和代谢调节到肿瘤细胞生长和转移。迄今为止，还没有针对 FTD 的疾病改善疗法，但目前正在开发不同的治疗方法来提高中枢神经系统中的 GRN 水平（包括 AAV 介导的 GRN 基因递送以及抗 SORT1 抗体疗法）。在这次审查中，我们概述了 GRN 水平的多方面调节和相应的治疗途径。我们讨论了各种方法的机会、优点和潜在缺点。此外，我们强调了将 GRN 水平提高到 GRN 功能丧失突变患者之外的治疗潜力。