Evidence map›Paper›PMID 34686711›Full record

ArticleScientific reports2021

Preclinical pharmacology of glucosylceramide synthase inhibitor venglustat in a GBA-related synucleinopathy model.

Catherine Viel, Jennifer Clarke, Can Kayatekin, Amy M Richards, Ming Sum R Chiang, Hyejung Park, Bing Wang, Lamya S Shihabuddin, S Pablo Sardi

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

Article in Scientific reports, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
14citing papers in PubMed, 1 pooled it
2.4field-weighted citation impact, top 11% 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

14 citing papers in PubMed, 1 synthesis or guideline pooled it, 26 citations in OpenAlex.

  1. Pooled it
  2. Review
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  5. Article
  6. Review
  7. A PIKfyve modulator combined with an integrated stress response inhibitor to treat lysosomal storage diseases.Proceedings of the National Academy of Sciences of the United States of America · 2024
    Article
  8. Article
  9. Article
  10. Article
  11. Neuronopathic GBA1L444P Mutation Accelerates Glucosylsphingosine Levels and Formation of Hippocampal Alpha-Synuclein Inclusions.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2023
    Article
  12. Review
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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

9 authors at 1 institution in 1 country.

Catherine VielRare and Neurologic Diseases, Sanofi, 49 New York Avenue, Framingham, MA, 01701, USA.
Jennifer ClarkeRare and Neurologic Diseases, Sanofi, 49 New York Avenue, Framingham, MA, 01701, USA.
Can KayatekinRare and Neurologic Diseases, Sanofi, 49 New York Avenue, Framingham, MA, 01701, USA.
Amy M RichardsGenomic Medicine Unit, Sanofi, Framingham, MA, 01701, USA.
Ming Sum R ChiangRare and Neurologic Diseases, Sanofi, 49 New York Avenue, Framingham, MA, 01701, USA.
Hyejung ParkUS Early Development for Synthetics Platform, Sanofi, Waltham, MA, 02451, USA.
Bing WangUS Early Development for Synthetics Platform, Sanofi, Waltham, MA, 02451, USA.
Lamya S ShihabuddinRare and Neurologic Diseases, Sanofi, 49 New York Avenue, Framingham, MA, 01701, USA.
S Pablo SardiRare and Neurologic Diseases, Sanofi, 49 New York Avenue, Framingham, MA, 01701, USA. pablo.sardi@sanofi.com.
Sanofi (United States) · US

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

Mutations in GBA, the gene encoding the lysosomal enzyme glucocerebrosidase (GCase), represent the greatest genetic risk factor for developing synucleinopathies including Parkinson's disease (PD). Additionally, PD patients harboring a mutant GBA allele present with an earlier disease onset and an accelerated disease progression of both motor and non-motor symptoms. Preclinical studies in mouse models of synucleinopathy suggest that modulation of the sphingolipid metabolism pathway via inhibition of glucosylceramide synthase (GCS) using a CNS-penetrant small molecule may be a potential treatment for synucleinopathies. Here, we aim to alleviate the lipid storage burden by inhibiting the de novo synthesis of the primary glycosphingolipid substrate of GCase, glucosylceramide (GlcCer). We have previously shown that systemic GCS inhibition reduced GlcCer and glucosylsphingosine (GlcSph) accumulation, slowed α-synuclein buildup in the hippocampus, and improved cognitive deficits. Here, we studied the efficacy of a brain-penetrant clinical candidate GCS inhibitor, venglustat, in mouse models of GBA-related synucleinopathy, including a heterozygous Gba mouse model which more closely replicates the typical GBA-PD patient genotype. Collectively, these data support the rationale for modulation of GCase-related sphingolipid metabolism as a therapeutic strategy for treating GBA-related synucleinopathies.

Indexed as

AnimalsCarbamatesDisease Models, AnimalGlucosylceramidaseGlucosylceramidesGlucosyltransferasesHippocampusMiceMice, Inbred C57BLMutationParkinson DiseaseQuinuclidinesSynucleinopathiesCarbamatesceramide glucosyltransferaseGba protein, mouseGlucosylceramidaseGlucosylceramidesGlucosyltransferasesQuinuclidinesvenglustat

Identifiers

PMID34686711
PMCPMC8536659
OpenAlexW3205560232

What OpenQuestion holds

Textmetadata
LicenceCC BY
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.