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

Apr 28, 2026Neurobiology of disease

Human-like mice with a harmful GRN gene deletion as a model for testing gene therapies in frontotemporal dementia

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Abstract

Achieving 8.5% correction of the progranulin gene in target cells was demonstrated using a novel mouse model.

Frontotemporal dementia (FTD) is associated with haploinsufficiency of the progranulin gene (GRN), but effective therapies are lacking.
A novel mouse strain was developed that expresses a human GRN transgene with a mutation linked to FTD.
The mutant GRN transgene is expressed at low levels and retains partial function, which helps mitigate some neurological issues.
The new mouse model allows for pre-clinical development of gene therapies targeting GRN.
The use of CRISPR/Cas9 with lipid nanoparticles enabled effective gene editing in the new mouse model.

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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) that causes FTD. Characterization of mice expressing the mutant transgene (GRN) indicates that GRNis expressed at low levels and retains partial function. The GRNprotein partially rescues progranulin nullizygous-associated neuropathology and transcriptomic dysfunction. Following characterization, we sought to determine if mice expressing GRNin the absence of mouse progranulin (Grn; GRNmice) could enable pre-clinical gene therapy development. Using CRISPR/Cas9 with lipid nanoparticle delivery, we achieved 8.5% correction of GRNin target cells in Grn; GRNmice, demonstrating both effective in vivo homology-directed repair and the utility of Grn; GRNmice for developing novel progranulin-associated FTD therapies. The Grn; GRNmodel provides insight into progranulin biology, increases our understanding of a pathogenic variant that causes FTD, and facilitates the development of GRN gene therapies. c.388_391delCAGT mEx5mEx5mEx5mEx5 -/-mEx5c.388_391delCAGT -/-mEx5 -/-mEx5 -/-mEx5

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

Abstract

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