Tweaking Progranulin Expression: Therapeutic Avenues and Opportunities.

Joke Terryn,Catherine M Verfaillie,Philip Van Damme

doi:10.3389/fnmol.2021.713031

Joke Terryn, Catherine M Verfaillie + Show 1 more

Open Access

https://doi.org/10.3389/fnmol.2021.713031

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Abstract

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.

Highlights

FTD-amyotrophic lateral sclerosis (ALS) Spectrum DisordersFrontotemporal dementia (FTD) is a neurodegenerative disease, leading to behavioral changes and language difficulties
Significant progress has been made towards the development of therapies modulating GRN levels
With a common goal to raise GRN levels, every therapeutic intervention differs in the extent of action depending on the biological strategy used and by mode of administration

Summary

Introduction

FTD-ALS Spectrum DisordersFrontotemporal dementia (FTD) is a neurodegenerative disease, leading to behavioral changes and language difficulties. Several studies showed that patients with a GRN mutation have reduced GRN protein levels in the cerebrospinal fluid (Ghidoni et al, 2008; Van Damme et al, 2008). GRN haploinsufficiency in the brain, as seen in FTD cases with GRN mutations, leads to chronic degenerative changes of neuronal loss, gliosis, and microglial activation (Mackenzie et al, 2006).

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