Humanized mice carrying a pathogenic GRN deletion as a pre-clinical platform for targeted gene therapies in frontotemporal dementia

Haploinsufficiency of the gene progranulin (GRN) is a major cause of frontotemporal dementia (FTD), for which there are no effective therapies. We developed a novel strain of mice expressing a human GRN transgene bearing a four base pair deletion in exon 5 (GRNc.388_391delCAGT) that causes FTD. Characterization of mice expressing the mutant transgene (GRNmEx5) indicates that GRNmEx5 is expressed at low levels and retains partial function. The GRNmEx5 protein partially rescues progranulin nullizygous-associated neuropathology and transcriptomic dysfunction. The Grn-/-; GRNmEx5 model provides insight into progranulin biology, increases our understanding of a pathogenic variant that causes FTD, and facilitates the development of GRN gene therapies.