Evidence map›Paper›PMID 38643236›Full record

ArticleScientific reports2024

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

Zachary C Rosenthal, Daniel M Fass, N Connor Payne, Angela She, Debasis Patnaik, Krista M Hennig, Rachel Tesla, Gordon C Werthmann, Charlotte Guhl, Surya A Reis and 8 more

Open access · goldAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Scientific reports, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.

0numbers the graph read from it
0cells of the map it votes in
8citing papers in PubMed
2.3field-weighted citation impact, top 12% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

8 citing papers in PubMed, 10 citations in OpenAlex.

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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

18 authors at 7 institutions in 2 countries.

Zachary C RosenthalChemical Neurobiology Laboratory, Precision Therapeutics Unit, Center for Genomic Medicine, Departments of Neurology and Psychiatry, Harvard Medical School, Massachusetts General Hospital, Boston, MA, USA.
Daniel M FassChemical Neurobiology Laboratory, Precision Therapeutics Unit, Center for Genomic Medicine, Departments of Neurology and Psychiatry, Harvard Medical School, Massachusetts General Hospital, Boston, MA, USA.
N Connor PayneDepartment of Chemistry & Chemical Biology, Harvard University, Cambridge, MA, USA.
Angela SheChemical Neurobiology Laboratory, Precision Therapeutics Unit, Center for Genomic Medicine, Departments of Neurology and Psychiatry, Harvard Medical School, Massachusetts General Hospital, Boston, MA, USA.
Debasis PatnaikChemical Neurobiology Laboratory, Precision Therapeutics Unit, Center for Genomic Medicine, Departments of Neurology and Psychiatry, Harvard Medical School, Massachusetts General Hospital, Boston, MA, USA.
Krista M HennigChemical Neurobiology Laboratory, Precision Therapeutics Unit, Center for Genomic Medicine, Departments of Neurology and Psychiatry, Harvard Medical School, Massachusetts General Hospital, Boston, MA, USA.
Rachel TeslaDepartment of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Gordon C WerthmannDepartment of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Charlotte GuhlFaculty of Chemistry and Earth Sciences, Institute of Organic Chemistry and Macromolecular Chemistry, Friedrich Schiller University Jena, Jena, Germany.
Surya A ReisChemical Neurobiology Laboratory, Precision Therapeutics Unit, Center for Genomic Medicine, Departments of Neurology and Psychiatry, Harvard Medical School, Massachusetts General Hospital, Boston, MA, USA.
Xiaoyu WangDepartment of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Yueting ChenDepartment of Radiology, Harvard Medical School, Boston, MA, USA.
Michael PlaczekDepartment of Radiology, Harvard Medical School, Boston, MA, USA.
Noelle S WilliamsDepartment of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Jacob HookerDepartment of Radiology, Harvard Medical School, Boston, MA, USA.
Joachim HerzDepartment of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Ralph MazitschekCenter for Systems Biology, Massachusetts General Hospital, Boston, MA, USA.
Stephen J HaggartyChemical 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.
Harvard University · USThe University of Texas Southwestern Medical Center · USMassachusetts General Hospital · USAthinoula A. Martinos Center for Biomedical Imaging · USBroad Institute · USFriedrich Schiller University Jena · DEPrecision Therapeutics (United States) · US

Funding

Validation of Modulators of PGRN as Novel Therapeutics for Frontotemporal DementiR01NS108115 · NINDS · UT SOUTHWESTERN MEDICAL CENTER · PI HAGGARTY, STEPHEN J, HERZ, JOACHIM J · 2018 to 2022
$4.0M
NINDS NIH HHS R01 NS108115NINDS NIH HHS R01NS108115
6 · The paper itself

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.

Indexed as

Frontotemporal DementiaBromodomain Containing ProteinsCell Cycle ProteinsEpigenesis, GeneticHumansIntercellular Signaling Peptides and ProteinsMutationNuclear ProteinsProgranulinsTranscription FactorsBRD4 protein, humanBromodomain Containing ProteinsCell Cycle ProteinsIntercellular Signaling Peptides and ProteinsNuclear ProteinsProgranulinsTranscription Factors

Identifiers

PMID38643236
PMCPMC11032351
OpenAlexW4394976565

What OpenQuestion holds

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LicenceCC BY
Read underepoch 390

Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.