Evidence map›Paper›PMID 31208914›Full record

ArticleMolecular therapy : the journal of the American Society of Gene Therapy2019

Substrate Reduction Therapy for Sandhoff Disease through Inhibition of Glucosylceramide Synthase Activity.

John Marshall, Jennifer B Nietupski, Hyejung Park, James Cao, Dinesh S Bangari, Cristina Silvescu, Terry Wilper, Kristen Randall, Drew Tietz, Bing Wang and 3 more

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

Article in Molecular therapy : the journal of the American Society of Gene Therapy, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.

0numbers the graph read from it
0cells of the map it votes in
35citing papers in PubMed
3.4field-weighted citation impact, top 7% 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

35 citing papers in PubMed, 55 citations in OpenAlex.

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  20. Gene Therapy of Sphingolipid Metabolic Disorders.International journal of molecular sciences · 2023
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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

13 authors at 1 institution in 1 country.

John MarshallSanofi, 49 New York Avenue, Framingham, MA 01701, USA. Electronic address: ramhoj@usa.net.
Jennifer B NietupskiSanofi, 49 New York Avenue, Framingham, MA 01701, USA.
Hyejung ParkSanofi, 49 New York Avenue, Framingham, MA 01701, USA.
James CaoSanofi, 49 New York Avenue, Framingham, MA 01701, USA.
Dinesh S BangariSanofi, 49 New York Avenue, Framingham, MA 01701, USA.
Cristina SilvescuSanofi, 49 New York Avenue, Framingham, MA 01701, USA.
Terry WilperSanofi, 49 New York Avenue, Framingham, MA 01701, USA.
Kristen RandallSanofi, 49 New York Avenue, Framingham, MA 01701, USA.
Drew TietzSanofi, 49 New York Avenue, Framingham, MA 01701, USA.
Bing WangSanofi, 49 New York Avenue, Framingham, MA 01701, USA.
Xiaoyou YingSanofi, 49 New York Avenue, Framingham, MA 01701, USA.
John P LeonardSanofi, 49 New York Avenue, Framingham, MA 01701, USA.
Seng H ChengSanofi, 49 New York Avenue, Framingham, MA 01701, USA. Electronic address: seng.cheng@pfizer.com.
Sanofi (United States) · US

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

Neuronopathic glycosphingolipidoses are a sub-group of lysosomal storage disorders for which there are presently no effective therapies. Here, we evaluated the potential of substrate reduction therapy (SRT) using an inhibitor of glucosylceramide synthase (GCS) to decrease the synthesis of glucosylceramide (GL1) and related glycosphingolipids. The substrates that accumulate in Sandhoff disease (e.g., ganglioside GM2 and its nonacylated derivative, lyso-GM2) are distal to the drug target, GCS. Treatment of Sandhoff mice with a GCS inhibitor that has demonstrated CNS access (Genz-682452) reduced the accumulation of GL1 and GM2, as well as a variety of disease-associated substrates in the liver and brain. Concomitant with these effects was a significant decrease in the expression of CD68 and glycoprotein non-metastatic melanoma B protein (Gpnmb) in the brain, indicating a reduction in microgliosis in the treated mice. Moreover, using in vivo imaging, we showed that the monocytic biomarker translocator protein (TSPO), which was elevated in Sandhoff mice, was normalized following Genz-682452 treatment. These positive effects translated in turn into a delay (∼28 days) in loss of motor function and coordination, as measured by rotarod latency, and a significant increase in longevity (∼17.5%). Together, these results support the development of SRT for the treatment of gangliosidoses, particularly in patients with residual enzyme activity.

Indexed as

Animalsbeta-Hexosaminidase beta ChainBrainCarbamatesDisease Models, AnimalEnzyme InhibitorsFemaleGlucosyltransferasesLigandsLiverMaleMass SpectrometryMiceMice, KnockoutMolecular ImagingQuinuclidinesbeta-Hexosaminidase beta ChainBzrp protein, mouseCarbamatesceramide glucosyltransferaseEnzyme InhibitorsGlucosyltransferasesLigandsQuinuclidinesReceptors, GABASphingolipidsvenglustatglucosylceramide synthaseglycosphingolipidGM2 gangliosidosisin vivo imaginglysosomal storage disorderSandhoff diseasesubstrate reduction therapytissue mass spectrometry imaging

Identifiers

PMID31208914
PMCPMC6697407
OpenAlexW2948188928

What OpenQuestion holds

Textmetadata
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.