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Effects of the investigational drug sodium phenylbutyrate-TUDCA (AMX0035) on the transcriptional and metabolic landscape of sporadic ALS fibroblasts

Fels, Jasmine A. and Dash, Jalia and Leslie, Kent and Manfredi, Giovanni and Kawamata, Hibiki (2022) Effects of the investigational drug sodium phenylbutyrate-TUDCA (AMX0035) on the transcriptional and metabolic landscape of sporadic ALS fibroblasts. . (Unpublished) https://resolver.caltech.edu/CaltechAUTHORS:20220510-534998800

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Abstract

ALS is a rapidly progressive, fatal disorder caused by motor neuron degeneration, for which there is a great unmet therapeutic need. AMX0035, a combination of sodium phenylbutyrate (PB) and taurursodiol (TUDCA, Turso), has shown promising results in early ALS clinical trials, but its mechanisms of action remain to be elucidated. To obtain an unbiased landscape of AMX0035 effects we investigated the transcriptomic and metabolomic profiles of primary skin fibroblasts from sporadic ALS patients and healthy controls treated with PB, TUDCA, or PB-TUDCA combination (Combo). Combo changed many more genes and metabolites than either PB or TUDCA individually. Most changes were unique to Combo and affected the expression of genes involved in ALS-relevant pathways, such as nucleocytoplasmic transport, unfolded protein response, mitochondrial function, RNA metabolism, and innate immunity. Weighted gene coexpression network analysis showed that significant correlations between ALS gene expression modules and clinical parameters were abolished by Combo. This study is the first to explore the molecular effects of Combo in ALS patient-derived cells. It shows that Combo has a greater and distinct impact compared to the individual compounds and provides clues to drug targets and mechanisms of actions, which may underlie the benefits of this investigational drug combination.


Item Type:Report or Paper (Discussion Paper)
Related URLs:
URLURL TypeDescription
https://doi.org/10.1101/2022.05.02.490306DOIDiscussion Paper
Additional Information:The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license. This version posted May 2, 2022. We thank Amylyx Pharmaceuticals for providing the compounds used for this study. We thank Dr. Hiroshi Mitsumoto (Columbia University) and the COSMOS initiative for providing the fibroblast and plasma samples utilized in this work. We acknowledge the contribution of the Weill Cornell Genomics Resource Core Facility, and the Medicine Meyer Cancer Center Proteomics & Metabolomics Core Facility. This work was supported by funds from NIH/NINDS grant R35 NS122209 (to GM) and R21 NS104520 (To HK and GM). Competing Interest Statement: This work was supported in part by a sponsored research agreement with Amylyx Pharmaceuticals. At the time when the work was performed KL was employed by Amylyx.
Funders:
Funding AgencyGrant Number
NIHR35 NS122209
NIHR21 NS104520
Subject Keywords:ALS, fibroblasts, AMX0035, Turso, Phenylbutyrate, WGCNA, RNAseq, metabolomics
DOI:10.1101/2022.05.02.490306
Record Number:CaltechAUTHORS:20220510-534998800
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20220510-534998800
Official Citation:Effects of the investigational drug sodium phenylbutyrate-TUDCA (AMX0035) on the transcriptional and metabolic landscape of sporadic ALS fibroblasts. Jasmine A. Fels, Jalia Dash, Kent Leslie, Giovanni Manfredi, Hibiki Kawamata. bioRxiv 2022.05.02.490306; doi: https://doi.org/10.1101/2022.05.02.490306
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:114666
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:10 May 2022 22:37
Last Modified:10 May 2022 22:37

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