Preclinical Interventions in Mouse Models of Frontotemporal Dementia Due to Progranulin Mutations

Abstract

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.

Granulins rescue inflammation, lysosome dysfunction, and neuropathology in a mouse model of progranulin deficiency.

“…The findings from our work have important implications for therapeutic development to treat FTD-GRN and other neurodegenerative diseases with PGRN deficiency. Multiple therapeutic strategies to increase PGRN levels in the CNS are being pursued for clinical development ranging from protein replacement 12 , to gene therapy 66 , and small molecule approaches. 67 One approach aims to increase PGRN by depleting sortilin (SORT1), a PGRN lysosomal trafficking receptor, with an antibody (AL001) that has advanced to a phase 3 clinical trial (NCT04374136).…”

Biochemical, biomarker, and behavioral characterization of theGrnR493Xmouse model of frontotemporal dementia

“…Notably, all of these phenotypes have also been observed in mouse models of NCL [30,74-77], raising the possibility that these observed phenotypes in homozygous Grn knockout and Grn R493X mice may reflect NCL rather than FTD- GRN . Our results support that, despite their more subtle phenotype, heterozygous Grn +/- and Grn +/R493X mice are likely to be more appropriate models of FTD- GRN than the homozygous mice, as previously suggested [35,78].…”

CNS Repopulation by Hematopoietic-Derived Microglia-Like Cells Corrects Progranulin deficiency

“…CLN11/FTD represents a critical unmet need and is potentially amenable to protein, gene, and cell therapy approaches. However, the effectiveness of these approaches is challenged by the difficulty in delivering the large GRN protein across the blood-brain barrier (BBB), achieving widespread GRN distribution in the CNS 45 – 48 , and by potential complications of supraphysiological or ectopic GRN expression 47 , 49 .…”