Evidence map›Paper›PMID 39894457›Full record

ArticleBritish journal of pharmacology2025

Assessment of Spinster homologue 2 (Spns2)-dependent transport of sphingosine-1-phosphate as a therapeutic target.

Yugesh Kharel, Tao Huang, Kyle Dunnavant, Daniel Foster, George M P R Souza, Katherine E Nimchuk, Andrea R Merchak, Caitlin M Pavelec, Zuzanna J Juskiewicz, Simon S Alexander and 8 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in British journal of pharmacology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.

0numbers the graph read from it
0cells of the map it votes in
1citing papers in PubMed
–field-weighted citation impact
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

1 citing paper in PubMed.

  1. Article
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.

Yugesh KharelDepartment of Pharmacology, University of Virginia, Charlottesville, Virginia, USA.
Tao HuangDepartment of Pharmacology, University of Virginia, Charlottesville, Virginia, USA.
Kyle DunnavantDepartment of Chemistry and Virginia Tech Center for Drug Discovery, Virginia Tech, Blacksburg, Virginia, USA.
Daniel FosterDepartment of Chemistry and Virginia Tech Center for Drug Discovery, Virginia Tech, Blacksburg, Virginia, USA.
George M P R SouzaDepartment of Pharmacology, University of Virginia, Charlottesville, Virginia, USA.
Katherine E NimchukDepartment of Neuroscience, University of Virginia, Charlottesville, Virginia, USA.
Andrea R MerchakDepartment of Neuroscience, University of Virginia, Charlottesville, Virginia, USA.
Caitlin M PavelecDepartment of Pharmacology, University of Virginia, Charlottesville, Virginia, USA.
Zuzanna J JuskiewiczRobert M. Berne Cardiovascular Research Center and Department of Molecular Physiology and Biophysics, University of Virginia, Charlottesville, Virginia, USA.
Simon S AlexanderDepartment of Pharmacology, University of Virginia, Charlottesville, Virginia, USA.
Alban GaultierDepartment of Neuroscience, University of Virginia, Charlottesville, Virginia, USA.
Stephen B G AbbottDepartment of Pharmacology, University of Virginia, Charlottesville, Virginia, USA.
Jung-Bum ShinDepartment of Neuroscience, University of Virginia, Charlottesville, Virginia, USA.
Brant E IsaksonRobert M. Berne Cardiovascular Research Center and Department of Molecular Physiology and Biophysics, University of Virginia, Charlottesville, Virginia, USA.
Wehao XuDepartment of Microbiology, Immunology and Cancer Biology and Genetically Engineered Murine Model Core, University of Virginia, Charlottesville, Virginia, USA.
Norbert LeitingerDepartment of Pharmacology, University of Virginia, Charlottesville, Virginia, USA.
Webster L SantosDepartment of Chemistry and Virginia Tech Center for Drug Discovery, Virginia Tech, Blacksburg, Virginia, USA.
Kevin R LynchDepartment of Pharmacology, University of Virginia, Charlottesville, Virginia, USA.ORCID https://orcid.org/0000-0002-7376-922X

Funding

BASIC CARDIOVASCULAR RESEARCH TRAINING GRANTT32HL007284 · NHLBI · UNIVERSITY OF VIRGINIA CHARLOTTESVILLE · PI Brant E Isakson, Gary K Owens · 1985 to 2026
$19.6M
Purinergic Regulation of Veinous Endothelial PermeabilityR01HL137112 · NHLBI · UNIVERSITY OF VIRGINIA · PI Brant E Isakson, MICHAEL H. KOVAL · 2018 to 2026
$4.7M
Controlling the flux of sphingosine-1-phosphate in vivoR01AI144026 · NIAID · UNIVERSITY OF VIRGINIA · PI LYNCH, KEVIN R., SANTOS, WEBSTER L · 2019 to 2023
$3.5M
Significance of Myo7a isoforms in hair cell functionR01DC018842 · NIDCD · UNIVERSITY OF VIRGINIA · PI Jung-Bum Shin · 2020 to 2026
$2.9M
Understanding the impact of Clusterin on the oligodendrocyte lineage in ADRF1AG079520 · NIA · UNIVERSITY OF VIRGINIA · PI GAULTIER, ALBAN P · 2022 to 2025
$2.7M
Role of presympathetic neurons of the hindbrain in cardiovascular controlR01HL148004 · NHLBI · UNIVERSITY OF VIRGINIA · PI ABBOTT, STEPHEN · 2019 to 2023
$2.6M
Blockade of S1P pathway for renal fibrosis therapyR01DK137181 · NIDDK · VIRGINIA POLYTECHNIC INST AND ST UNIV · PI KEVIN R. LYNCH, Webster L Santos · 2024 to 2026
$1.8M
Machine learning-based multi-omics modeling and CRISPR/Cas9-mediated gene editing in elucidating molecular transducer of physical activityU01AG070960 · NIA · VIRGINIA POLYTECHNIC INST AND ST UNIV · PI YAN, ZHEN · 2020 to 2022
$1.5M
Brain, Immunology and Glia Training ProgramT32NS115657 · NINDS · UNIVERSITY OF VIRGINIA · PI Alban P Gaultier, TAJIE H. HARRIS · 2021 to 2026
$1.2M
Metabolic adaption of macrophages to heme detoxification in systemic vascular inflammationR56HL158886 · NHLBI · UNIVERSITY OF VIRGINIA · PI LEITINGER, NORBERT · 2022 to 2022
$517k
A CRISPR-based modular transgenic system to advance in vivo investigations of angiogenesis and fibrosisR21OD032144 · OD · UNIVERSITY OF VIRGINIA · PI WOLF, MATTHEW J · 2022 to 2023
$444k
A role for cardiomyocyte pannexin 1 in non-ischemic heart failureF31HL165918 · NHLBI · UNIVERSITY OF VIRGINIA · PI PAVELEC, CAITLIN MARIE · 2023 to 2023
$27k
NHLBI NIH HHS F31 HL165918NHLBI NIH HHS R01 HL137112NHLBI NIH HHS R01 HL148004NHLBI NIH HHS R56 HL158886NHLBI NIH HHS T32 HL007284NIAID NIH HHS F31 AI174782NIAID NIH HHS R01 AI144026NIA NIH HHS RF1 AG079520NIA NIH HHS U01 AG070960NIDCD NIH HHS R01 DC018842NIDDK NIH HHS R01 DK137181NIH HHS R21 OD032144NINDS NIH HHS T32 NS115657US/DHHS/PHS/NIH F31AI174782US/DHHS/PHS/NIH F31HL165918US/DHHS/PHS/NIH R01AI144026US/DHHS/PHS/NIH R01DC018842US/DHHS/PHS/NIH R01HL137112US/DHHS/PHS/NIH R01HL148004US/DHHS/PHS/NIH R01HL165143US/DHHS/PHS/NIH R21OD032144US/DHHS/PHS/NIH R56HL158886US/DHHS/PHS/NIH RF1AG079520US/DHHS/PHS/NIH T32HL007284US/DHHS/PHS/NIH T32NS115657US/DHHS/PHS/NIH U01AG070960Virginia Commonwealth Commercialization Fund CCF24-0018-HE
6 · The paper itself

Abstract

background and purposeSphingosine-1-phosphate (S1P) receptor modulator (SRM) drugs suppress immune system function by disrupting lymphocyte trafficking, but SRMs are broadly immunosuppressive with on-target liabilities. Another strategy to modulate the immune system is to block S1P transport. This study tests the hypothesis that blockers of S1P transport (STBs) mediated by Spinster homologue 2 (Spns2) approximate the efficacy of SRMs without their adverse events. EXPERIMENTAL APPROACH: We have discovered and optimized STBs to enable investigations of S1P biology and to determine whether S1P transport is a valid drug target. The STB SLF80821178 was administered to rodents to assess its efficacy in a multiple sclerosis model and to test for toxicities associated with SRMs or Spns2-deficient mice. Further, potential biomarkers of STBs, absolute lymphocyte counts (ALCs) in blood and S1P concentrations in plasma and lymph, were measured. KEY

resultsSLF80821178 resembles SRMs in that it is efficacious in a standard multiple sclerosis model but does not evoke bradycardia or lung leakage, common to the SRM drug class. Also, chronic SLF80821178 administration does not affect auditory responses in adult mice despite the neurosensorial hearing defect observed in Spns2-null mice. While both SRM and STB administration decrease ALCs, the maximal effect is less with an STB (45% vs. 90%). STBs have minimal effects on S1P concentration in plasma or thoracic duct lymph. CONCLUSION AND IMPLICATIONS: We found nothing to invalidate Spns2-dependent S1P transport as a drug target. Indeed, STBs could be superior to SRMs as a therapy to modulate immune system function.

Indexed as

Anion Transport ProteinsLysophospholipidsSphingosineSphingosine 1 Phosphate Receptor ModulatorsAnimalsBiological TransportEncephalomyelitis, Autoimmune, ExperimentalFemaleHumansImmunosuppressive AgentsMaleMiceMice, Inbred C57BLMice, KnockoutMultiple SclerosisRatsAnion Transport ProteinsImmunosuppressive AgentsLysophospholipidsSphingosinesphingosine 1-phosphateSphingosine 1 Phosphate Receptor ModulatorsSpns2 protein, mouseS1P receptor modulatorsS1P transportS1P transport blockerssphingosine 1‐phosphate(S1P)Spns2

Identifiers

PMID39894457
PMCPMC12034028

What Socratic holds

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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 Socratic graph.