Carboxyl-terminal blockade of sortilin binding enhances progranulin gene therapy in a mouse model of frontotemporal dementia.

Frontotemporal dementia is commonly caused by loss-of-function mutations in the progranulin gene. Potential therapies for this disorder have entered clinical trials, including progranulin gene therapy and drugs that reduce progranulin interactions with sortilin. Both approaches ameliorate functional and pathological abnormalities in mouse models of progranulin insufficiency. Here, we investigated whether modifying the progranulin carboxyl terminus to block sortilin interactions would improve the efficacy of progranulin gene therapy. We compared the effects of treating progranulin-deficient mice with gene therapy vectors expressing progranulin with intact sortilin interactions, progranulin with the carboxyl terminus blocked to reduce sortilin interactions, or GFP control. We found that expressing carboxyl-terminally blocked progranulin generated higher levels of progranulin both at the injection site and in more distant regions. Carboxyl-terminally blocked progranulin was also more effective at ameliorating microgliosis, microglial lipofuscinosis, microglial morphology changes, and lipid abnormalities including ganglioside accumulation and loss of bis(monoacylglycero)phosphate lipids. Behavioral abnormalities detected in progranulin-deficient mice using an unbiased machine learning analysis were absent after treatment with carboxyl-terminally blocked progranulin but not corrected by unblocked progranulin. Last, only carboxyl-terminally blocked progranulin reduced plasma neurofilament light chain, a biomarker of axonal damage, in progranulin-deficient mice. These results demonstrate that modifying the progranulin cargo to block sortilin interactions may be important for increasing the effectiveness of progranulin gene therapy.