The granulin protein (also known as, and hereafter referred to as, progranulin) 
is a secreted glycoprotein that contributes to overall brain health. 
Heterozygous loss-of-function mutations in the gene encoding the progranulin 
protein (Granulin Precursor, GRN) are a common cause of familial frontotemporal 
dementia (FTD). Gene therapy approaches that aim to increase progranulin 
expression from a single wild-type allele, an area of active investigation for 
the potential treatment of GRN-dependent FTD, will benefit from the availability 
of a mouse model that expresses a genomic copy of the human GRN gene. Here we 
report the development and characterization of a novel mouse model that 
expresses the entire human GRN gene in its native genomic context as a single 
copy inserted into a defined locus (Hprt) in the mouse genome. We show that 
human and mouse progranulin are expressed in a similar tissue-specific pattern, 
suggesting that the two genes are regulated by similar mechanisms. Human 
progranulin rescues a phenotype characteristic of progranulin-null mice, the 
exaggerated and early deposition of the aging pigment lipofuscin in the brain, 
indicating that the two proteins are functionally similar. Longitudinal 
behavioural and neuropathological analyses revealed no significant differences 
between wild-type and human progranulin-overexpressing mice up to 18 months of 
age, providing evidence that long-term increase of progranulin levels is well 
tolerated in mice. Finally, we demonstrate that human progranulin expression can 
be increased in the brain using an antisense oligonucleotide that inhibits a 
known GRN-regulating micro-RNA, demonstrating that the transgene is responsive 
to potential gene therapy drugs. Human progranulin-expressing mice represent a 
novel and valuable tool to expedite the development of progranulin-modulating 
therapeutics.