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

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.

Unraveling the Heterogeneity of ALS—A Call to Redefine Patient Stratification for Better Outcomes in Clinical Trials

“…One of the two studies identified a group of patients categorized as “responders” [ 147 ]. Further studies, such as the clinical trial on low dose interleukin 2 (NCT02059759) and the AMX0035 trial, also tried to identify the molecular profiles of these so called “responders” [ 148 , 149 ]. Of course, the identification of responders would be specific to every single treatment, while cluster identification might be suitable for a more generalized usage.…”

Assessing the efficacy of amyotrophic lateral sclerosis drugs in slowing disease progression: A literature review

“…Currently, the drug's exact mechanism of action is not well understood. Though it is unknown how the drug exerts its therapeutic effect, it has been established that these two compounds work in conjunction to prevent nerve cell death by inhibiting stress signals within the cell's mitochondria and endoplasmic reticulum [17] . Taurursodiol alone is commonly used to treat chronic cholestatic liver diseases and gallstones due to its anti-apoptotic effects, which includes regulating the expression of specific targets of apoptosis and mitochondrial membrane stabilization [18] .…”

Small molecules targeting different cellular pathologies for the treatment of amyotrophic lateral sclerosis

“…The synthesis of the target molecules proceeds from commercially-available benzoic acids 22 or 23, which are first converted to the acid chloride before reaction with a library of synthetic-or commercially-derived anilines and benzyl amines (24)(25)(26)(27)(28)(29)(30)(31) to afford the iodoamide intermediates (32)(33)(34)(35)(36)(37)(38)(39)(40) in high yields without the need for purification (Scheme 3). The target ebselen analogues (19 and 41-48) were prepared by a copper catalyzed ring closing reaction of the iodoamide intermediates (32)(33)(34)(35)(36)(37)(38)(39)(40) in the presence of selenium powder. 73 The stabilizing effects of the molecules were measured against a SOD1 A4V/C6S double mutant in the DSF assay and the protein melting temperature differential (ΔT m ) was used to determine the change in thermal stability of the mutant SOD1 compared to that of the SMC-treated mutant SOD1.…”

“…Although the exact mechanism of action of this coformulation is unknown, preclinical studies suggest that both drugs act as chemical chaperones preventing misfolded protein formation and reduce endoplasmic reticulum (ER) stress. 38,39 The most common adverse events occurring in ≥5% of sodium phenylbutyrate/ taurursodiol coformulation recipients include diarrhoea, abdominal pain, nausea, constipation, fatigue, decreased appetite and dizziness. 40 Given that about 350,000 people are diagnosed with ALS worldwide annually 41 (about 15,000 people in the United States), there is an urgent need to discover new and effective therapies for its treatment.…”

“…This coformulation contains 3 g of sodium phenylbutyrate and 1 g of taurursodiol powder, and is used as an oral suspension. Although the exact mechanism of action of this coformulation is unknown, preclinical studies suggest that both drugs act as chemical chaperones preventing misfolded protein formation and reduce endoplasmic reticulum (ER) stress 38,39 . The most common adverse events occurring in ≥5% of sodium phenylbutyrate/taurursodiol coformulation recipients include diarrhoea, abdominal pain, nausea, constipation, fatigue, decreased appetite and dizziness 40 …”