Evidence map›Paper›PMID 33651103›Full record

ArticleThe Journal of experimental medicine2021

Preclinical validation of a potent γ-secretase modulator for Alzheimer's disease prevention.

Kevin D Rynearson, Moorthi Ponnusamy, Olga Prikhodko, Yuhuan Xie, Can Zhang, Phuong Nguyen, Brenda Hug, Mariko Sawa, Ann Becker, Brian Spencer and 14 more

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

Article in The Journal of experimental medicine, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 48 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
48citing papers in PubMed, 1 pooled it
8.8field-weighted citation impact, top 1% 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

48 citing papers in PubMed, 1 synthesis or guideline pooled it, 70 citations in OpenAlex.

  1. Pooled it
  2. Association of CSF AβNeurology · 2022
    Trial
  3. Review
  4. Review
  5. Review
  6. Article
  7. Review
  8. Review
  9. Review
  10. Review
  11. Review
  12. Review
  13. Article
  14. Review
  15. Review
  16. Article
  17. Air pollution amyloidogenesis is attenuated by the gamma-secretase modulator GSM-15606.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2024
    Article
  18. Review
  19. Article
  20. Review
4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

24 authors at 4 institutions in 1 country.

Kevin D RynearsonDepartment of Neurosciences, University of California, San Diego, La Jolla, CA.
Moorthi PonnusamyDepartment of Molecular Medicine and Byrd Alzheimer's Institute, University of South Florida, Morsani College of Medicine, Tampa, FL.
Olga PrikhodkoDepartment of Neurosciences, University of California, San Diego, La Jolla, CA.
Yuhuan XieDepartment of Neurosciences, University of California, San Diego, La Jolla, CA.
Can ZhangGenetics and Aging Research Unit, Department of Neurology, Massachusetts General Hospital, Charlestown, MA.
Phuong NguyenDepartment of Neurosciences, University of California, San Diego, La Jolla, CA.
Brenda HugVeterans Administration San Diego Healthcare System, La Jolla, CA.
Mariko SawaDepartment of Neurosciences, University of California, San Diego, La Jolla, CA.
Ann BeckerDepartment of Neurosciences, University of California, San Diego, La Jolla, CA.
Brian SpencerDepartment of Neurosciences, University of California, San Diego, La Jolla, CA.
Jazmin FlorioDepartment of Neurosciences, University of California, San Diego, La Jolla, CA.
Michael ManteDepartment of Neurosciences, University of California, San Diego, La Jolla, CA.
Bahar SalehiDepartment of Neurosciences, University of California, San Diego, La Jolla, CA.
Carlos AriasDepartment of Neurosciences, University of California, San Diego, La Jolla, CA.
Douglas GalaskoDepartment of Neurosciences, University of California, San Diego, La Jolla, CA.
Brian P HeadVeterans Administration San Diego Healthcare System, La Jolla, CA.
Graham JohnsonNuPharmAdvise, Sanbornton, NH.
Jiunn H LinBiopharm Consulting Partners, Ambler, PA.
Steven K DuddyIntegrated Nonclinical Development Solutions, Ann Arbor, MI.
Robert A RissmanDepartment of Neurosciences, University of California, San Diego, La Jolla, CA.
William C MobleyDepartment of Neurosciences, University of California, San Diego, La Jolla, CA.
Gopal ThinakaranDepartment of Molecular Medicine and Byrd Alzheimer's Institute, University of South Florida, Morsani College of Medicine, Tampa, FL.
Rudolph E TanziGenetics and Aging Research Unit, Department of Neurology, Massachusetts General Hospital, Charlestown, MA.
Steven L WagnerDepartment of Neurosciences, University of California, San Diego, La Jolla, CA.
University of California San Diego · USMassachusetts General Hospital · USUniversity of South Florida · USVA San Diego Healthcare System · US

Funding

TRANSGENICS AND PRESENILIN FUNCTIONP01AG015379 · NIA · BRIGHAM AND WOMEN'S HOSPITAL · PI TANZI, RUDOLPH EMILE · 1998 to 2023
$51.3M
Optimization and preclinical development of soluble gamma-secretase modulators for ADU01AG048986 · NIA · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI WAGNER, STEVEN LEE · 2016 to 2019
$5.1M
The role of elevated BIN1 expression in Alzheimer's diseaseRF1AG056061 · NIA · UNIVERSITY OF SOUTH FLORIDA · PI THINAKARAN, GOPAL · 2018 to 2018
$3.7M
Treating with Gamma-Secretase Modulators to Prevent Neurodegeneration in Mouse Models of Down Syndrome and Alzheimer DiseaseR01AG055523 · NIA · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI MOBLEY, WILLIAM C · 2018 to 2022
$3.2M
Cell autonomous and non-cell autonomous roles of the GWAS risk factor BIN1 in Alzheimer's disease neuropathologyRF1AG054223 · NIA · UNIVERSITY OF SOUTH FLORIDA · PI THINAKARAN, GOPAL · 2016 to 2016
$2.9M
Characterizing the roles of novel soluble GSMs in AD pathology.R01AG055784 · NIA · MASSACHUSETTS GENERAL HOSPITAL · PI ZHANG, CAN MARTIN · 2018 to 2022
$2.1M
Optimization of Soluble Gamma-secretase Modulators for the Treatment of AlzheimerU01NS074501 · NINDS · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI WAGNER, STEVEN LEE · 2011 to 2015
$1.4M
BLRD VA I01 BX003671NIA NIH HHS P01 AG015379NIA NIH HHS R01 AG055523NIA NIH HHS R01 AG055784NIA NIH HHS RF1 AG054223NIA NIH HHS RF1 AG056061NIA NIH HHS U01 AG048986NINDS NIH HHS U01 NS074501
6 · The paper itself

Abstract

A potent γ-secretase modulator (GSM) has been developed to circumvent problems associated with γ-secretase inhibitors (GSIs) and to potentially enable use in primary prevention of early-onset familial Alzheimer's disease (EOFAD). Unlike GSIs, GSMs do not inhibit γ-secretase activity but rather allosterically modulate γ-secretase, reducing the net production of Aβ42 and to a lesser extent Aβ40, while concomitantly augmenting production of Aβ38 and Aβ37. This GSM demonstrated robust time- and dose-dependent efficacy in acute, subchronic, and chronic studies across multiple species, including primary and secondary prevention studies in a transgenic mouse model. The GSM displayed a >40-fold safety margin in rats based on a comparison of the systemic exposure (AUC) at the no observed adverse effect level (NOAEL) to the 50% effective AUC or AUCeffective, the systemic exposure required for reducing levels of Aβ42 in rat brain by 50%.

Indexed as

Alzheimer DiseaseAmyloid beta-PeptidesAmyloid Precursor Protein SecretasesAnimalsCell Line, TumorDisease Models, AnimalDose-Response Relationship, DrugDrug Evaluation, PreclinicalFemaleHumansMacaca fascicularisMaleMiceMice, Inbred C57BLMice, TransgenicNeuroblastomaAmyloid beta-Peptidesamyloid beta-protein (1-42)Amyloid Precursor Protein SecretasesBPN-15606Peptide FragmentsPhenethylaminesPyridazines

Identifiers

PMID33651103
PMCPMC7931646
OpenAlexW3135208068

What OpenQuestion holds

Textmetadata
LicenceCC BY-NC-SA
Read underepoch 390

Registered trials

None linked

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.