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

Frontotemporal dementia (FTD) is an early onset dementia characterized by neuropathology and changes to patient behaviour. Haploinsufficiency of the gene progranulin ( GRN ) is a major cause of FTD, for which there are no effective therapies. Corrective gene therapies that restore GRN expression are of clinical interest, but current in vivo systems have limitations. We developed a novel strain of mice expressing a human GRN transgene bearing a four base pair deletion in exon 5 ( GRN c.388_391delCAGT ) that causes FTD. Characterization of mice expressing the mutant transgene ( GRN mEx5 ) indicates that GRN mEx5 is expressed at low levels and retains partial function. The GRN mEx5 protein partially rescues progranulin nullizygous-associated neuropathology and transcriptomic dysfunction. Following characterization, we sought to determine if mice expressing GRN mEx5 in the absence of mouse progranulin ( Grn −/− ; GRN mEx5 mice) could enable pre-clinical gene therapy development. Using CRISPR/Cas9 with lipid nanoparticle delivery, we achieved 8.5% correction of GRN c.388_391delCAGT in target cells in Grn −/− ; GRN mEx5 mice, demonstrating both effective in vivo homology-directed repair and the utility of Grn −/− ; GRN mEx5 mice for developing novel progranulin-associated FTD therapies. The Grn −/− ; GRN mEx5 model provides insight into progranulin biology, increases our understanding of a pathogenic variant that causes FTD, and facilitates the development of GRN gene therapies . • Grn −/− ; GRN mEx5 mice express human progranulin with a common FTD causing mutation. • The GRN mEx5 protein partially rescues neuropathology and transcriptomic dysfunction. • In vivo correction of an FTD causing mutation was achieved in 8.5% of target cells. • Grn −/− ; GRN mEx5 mice have utility in the development of novel GRN-FTD therapies.