Tweaking Progranulin Expression: Therapeutic Avenues and Opportunities

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 the 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 the 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. ; sponsorship: The authors were supported by grants from KU Leuven (C1-C14-17-107), Opening the Future Fund (KU Leuven), the Fund for Scientific Research Flanders (FWO-Flanders), the ALS Liga Belgium, the KU Leuven funds "Een Hart voor ALS'', "Laeversfonds voor ALS Onderzoek'' and the "Valery Perrier Race against ALS Fund'', the Alzheimer Research Foundation (SAO-FRA 2017/023 and SAO-FRA 2019/0014), The Alzheimer Association (AARG-NTF-19-616888), the Flemish Government initiated Flanders Impulse Program on Networks for Dementia Research (VIND 135043), Flanders Innovation and Enterpreneurship (IWT grants Project MinE and iPSCAF), the Belgian National Lottery, the Latran Foundation, the European Union's Horizon 2020 research and innovation programme (755094), and the European Union's ERA-Netfor Research Programmes on Rare Diseases (INTEGRALS). PVD holds a ...