2. Academic Validation
  3. Epigenetic modulation through BET bromodomain inhibitors as a novel therapeutic strategy for progranulin-deficient frontotemporal dementia

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

  • Sci Rep. 2024 Apr 20;14(1):9064. doi: 10.1038/s41598-024-59110-7.
Zachary C Rosenthal 1 2,  Daniel M Fass 1,  N Connor Payne 2 3 4,  Angela She 1,  Debasis Patnaik 1,  Krista M Hennig 1,  Rachel Tesla 5 6,  Gordon C Werthmann 5 6,  Charlotte Guhl 7,  Surya A Reis 1,  Xiaoyu Wang 8,  Yueting Chen 9 10,  Michael Placzek 9 10,  Noelle S Williams 8,  Jacob Hooker 9 10,  Joachim Herz 5 6 11 12,  Ralph Mazitschek 3 4 13,  Stephen J Haggarty 14
Affiliations

Affiliations

  • 1 Chemical Neurobiology Laboratory, Precision Therapeutics Unit, Center for Genomic Medicine, Departments of Neurology and Psychiatry, Harvard Medical School, Massachusetts General Hospital, Boston, MA, USA.
  • 2 Department of Chemistry & Chemical Biology, Harvard University, Cambridge, MA, USA.
  • 3 Center for Systems Biology, Massachusetts General Hospital, Boston, MA, USA.
  • 4 Harvard T.H. Chan School of Public Health, Boston, MA, USA.
  • 5 Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • 6 Center for Translational Neurodegeneration Research, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • 7 Faculty of Chemistry and Earth Sciences, Institute of Organic Chemistry and Macromolecular Chemistry, Friedrich Schiller University Jena, Jena, Germany.
  • 8 Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • 9 Department of Radiology, Harvard Medical School, Boston, MA, USA.
  • 10 Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Boston, MA, USA.
  • 11 Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • 12 Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • 13 Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • 14 Chemical Neurobiology Laboratory, Precision Therapeutics Unit, Center for Genomic Medicine, Departments of Neurology and Psychiatry, Harvard Medical School, Massachusetts General Hospital, Boston, MA, USA. shaggarty@mgh.harvard.edu.
PMID: 38643236 DOI: 10.1038/s41598-024-59110-7
Abstract

Frontotemporal 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.

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