Heterozygous loss-of-function mutations in
progranulin (GRN) cause
frontotemporal dementia (FTD), a leading cause of early-onset
dementia characterized clinically by behavioral, social, and language deficits. There are currently no FDA-approved
therapeutics for
FTD-GRN, but this has been an active area of investigation, and several approaches are now in clinical trials. Here, we review preclinical development of
therapies for
FTD-GRN with a focus on testing in mouse models. Since most
FTD-GRN-associated mutations cause
progranulin haploinsufficiency, these approaches focus on raising
progranulin levels. We begin by considering the disorders associated with altered
progranulin levels, and then review the basics of
progranulin biology including its lysosomal, neurotrophic, and immunomodulatory functions. We discuss mouse models of
progranulin insufficiency and how they have been used in preclinical studies on a variety of therapeutic approaches. These include approaches to raise
progranulin expression from the normal allele or facilitate
progranulin production by the mutant allele, as well as approaches to directly increase
progranulin levels by delivery across the blood-brain barrier or by gene therapy. Several of these approaches have entered clinical trials, providing hope that new
therapies for
FTD-GRN may be the next frontier in the treatment of
neurodegenerative disease.