A Novel In Vivo‐Active Small Molecule Inducer of Progranulin for the Treatment of Frontotemporal Dementia

AbstractBackgroundHeterozygous mutations in GRN that lead to haploinsufficiency of the progranulin (PGRN) protein cause the fatal neurodegenerative disease frontotemporal dementia (FTD‐GRN). Complete loss of PGRN, on the other hand, leads to an early onset lysosomal storage disorder, indicating a critical role for PGRN in the lysosome. Although its exact function is unknown, PGRN is both secreted and trafficked to the lysosome where it is processed into granulins. Lysosomal granulins are reported to modulate the activity of lysosomal enzymes. Currently there are no treatments for FTD‐GRN but restoring PGRN to normal levels is a promising therapeutic strategy.MethodsWe performed a small molecule screen in BV‐2 cells and identified novel compounds that increase progranulin secretion. Some of these molecules were further characterized in vivo to help determine an exposure‐response relationship.ResultsThrough structure activity relationship optimization, we improved the potency of compounds at increasing PGRN secretion from >2 mM down to <1 nM. Importantly, we found that lysosomal granulins are increased following compound treatment and that this effect is sustained beyond the secreted PGRN increase. Using an optimized brain‐penetrant compound with good pharmacokinetic properties, we established an exposure‐response relationship for PGRN changes in the CSF of non‐human primates, demonstrating an excellent in vitro‐in vivo correlation. Finally, we report that multi‐day dosing produced a sustained increase in PGRN in CSF over the course of the treatment period.ConclusionOverall, these data support further development of our novel small molecules for the treatment of FTD‐GRN.