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Research Article
Scott L. Friedman
Icahn School of Medicine at Mount Sinai, New York,
Corresponding Author
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Non-alcoholic steatohepatitis (NASH) is a rising health challenge, with no approved drugs. We used a computational drug repositioning strategy to uncover a novel therapy for NASH, identifying a GABA-B receptor agonist, AZD3355 (lesogaberan) previously evaluated as a therapy for esophageal reflux. AZD3355’s potential efficacy in NASH was tested in human stellate cells, human precision cut liver slices (hPCLS), and in vivo in a well-validated murine model of NASH. In human stellate cells AZD3355 significantly downregulated profibrotic gene and protein expression. Transcriptomic analysis of these responses identified key regulatory nodes impacted by AZD3355, including Myc, as well as MAP and ERK kinases. In PCLS, AZD3355 down-regulated collagen1α1, aSMA and TNF-a mRNA as well as secreted collagen1a1. In vivo, the drug significantly improved histology, profibrogenic gene expression, and tumor development in a robust murine model of NASH, which was comparable to activity of obeticholic acid, an advanced investigational therapy for this disease. These data identify a well-tolerated clinical stage asset as a novel therapy for human NASH through its hepatoprotective, anti-inflammatory and antifibrotic mechanisms of action. The approach validates computational methods to identify novel therapies in NASH in uncovering new pathways of disease development that can be rapidly translated into clinical trials.
Keywords
Fibrosis, NAFLD, hepatic stellate cell, drug repurposing, informatics, therapeutics
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Competing interest reported. Conflict of interest:
Leslie P. Cousens: Employees of AstraZeneca Pharmaceuticals
Björn Magnusson: Employees of AstraZeneca Pharmaceuticals
Anna Backmark: Employees of AstraZeneca Pharmaceuticals
Ryan Hicks: Employees of AstraZeneca Pharmaceuticals
This is a list of supplementary files associated with this preprint. Click to download.
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CURRENT STATUS: Under Review
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Posted 12 Apr, 2021
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Editorial decision: Major revision
On 27 May, 2021
Reviews received
Received 19 May, 2021
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Received 29 Apr, 2021
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On 29 Apr, 2021
Reviewers agreed
On 28 Apr, 2021
Reviewers invited
Invitations sent on 28 Apr, 2021
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On 08 Apr, 2021
Editor invited
On 07 Apr, 2021
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Subject Areas
Pathology
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This preprint is under consideration at Scientific Reports. A preprint is a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Learn more about In Review
Research Article
Scott L. Friedman
Icahn School of Medicine at Mount Sinai, New York,
Corresponding Author
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
Peer Review Timeline
CURRENT STATUS: Under Review
Version 1
Posted 12 Apr, 2021
No community comments so far
Editorial decision: Major revision
On 27 May, 2021
Reviews received
Received 19 May, 2021
Reviews received
Received 29 Apr, 2021
Reviewers agreed
On 29 Apr, 2021
Reviewers agreed
On 28 Apr, 2021
Reviewers invited
Invitations sent on 28 Apr, 2021
Editor assigned
On 08 Apr, 2021
Editor invited
On 07 Apr, 2021
Submission checks complete
On 06 Apr, 2021
First submitted
On 02 Apr, 2021
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
Subject Areas
Pathology
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Non-alcoholic steatohepatitis (NASH) is a rising health challenge, with no approved drugs. We used a computational drug repositioning strategy to uncover a novel therapy for NASH, identifying a GABA-B receptor agonist, AZD3355 (lesogaberan) previously evaluated as a therapy for esophageal reflux. AZD3355’s potential efficacy in NASH was tested in human stellate cells, human precision cut liver slices (hPCLS), and in vivo in a well-validated murine model of NASH. In human stellate cells AZD3355 significantly downregulated profibrotic gene and protein expression. Transcriptomic analysis of these responses identified key regulatory nodes impacted by AZD3355, including Myc, as well as MAP and ERK kinases. In PCLS, AZD3355 down-regulated collagen1α1, aSMA and TNF-a mRNA as well as secreted collagen1a1. In vivo, the drug significantly improved histology, profibrogenic gene expression, and tumor development in a robust murine model of NASH, which was comparable to activity of obeticholic acid, an advanced investigational therapy for this disease. These data identify a well-tolerated clinical stage asset as a novel therapy for human NASH through its hepatoprotective, anti-inflammatory and antifibrotic mechanisms of action. The approach validates computational methods to identify novel therapies in NASH in uncovering new pathways of disease development that can be rapidly translated into clinical trials.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Competing interest reported. Conflict of interest:
Leslie P. Cousens: Employees of AstraZeneca Pharmaceuticals
Björn Magnusson: Employees of AstraZeneca Pharmaceuticals
Anna Backmark: Employees of AstraZeneca Pharmaceuticals
Ryan Hicks: Employees of AstraZeneca Pharmaceuticals
This is a list of supplementary files associated with this preprint. Click to download.
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