Epigenetic modulation through BET bromodomain inhibitors as a novel therapeutic strategy for progranulin-deficient frontotemporal dementia

Author:

Rosenthal Zachary C.,Fass Daniel M.,Payne N. Connor,She Angela,Patnaik Debasis,Hennig Krista M.,Tesla Rachel,Werthmann Gordon C.,Guhl Charlotte,Reis Surya A.,Wang Xiaoyu,Chen Yueting,Placzek Michael,Williams Noelle S.,Hooker Jacob,Herz Joachim,Mazitschek Ralph,Haggarty Stephen J.

Abstract

AbstractFrontotemporal dementia (FTD) is a debilitating neurodegenerative disorder with currently no disease-modifying treatment options available. Mutations in GRN are one of the most common genetic causes of FTD, near ubiquitously resulting in progranulin (PGRN) haploinsufficiency. Small molecules that can restore PGRN protein to healthy levels in individuals bearing a heterozygous GRN mutation may thus have therapeutic value. Here, we show that epigenetic modulation through bromodomain and extra-terminal domain (BET) inhibitors (BETi) potently enhance PGRN protein levels, both intracellularly and secreted forms, in human central nervous system (CNS)-relevant cell types, including in microglia-like cells. In terms of potential for disease modification, we show BETi treatment effectively restores PGRN levels in neural cells with a GRN mutation known to cause PGRN haploinsufficiency and FTD. We demonstrate that BETi can rapidly and durably enhance PGRN in neural progenitor cells (NPCs) in a manner dependent upon BET protein expression, suggesting a gain-of-function mechanism. We further describe a CNS-optimized BETi chemotype that potently engages endogenous BRD4 and enhances PGRN expression in neuronal cells. Our results reveal a new epigenetic target for treating PGRN-deficient forms of FTD and provide mechanistic insight to aid in translating this discovery into therapeutics.

Funder

National Institute of Neurological Disorders and Stroke

Bluefield Project to Cure FTD

Publisher

Springer Science and Business Media LLC

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