Biological effects of sodium phenylbutyrate and taurursodiol in Alzheimer's disease.

INTRODUCTION: Sodium phenylbutyrate and taurursodiol (PB and TURSO) is hypothesized to mitigate endoplasmic reticulum stress and mitochondrial dysfunction, two of many mechanisms implicated in Alzheimer's disease (AD) pathophysiology. METHODS: The first-in-indication phase 2a PEGASUS trial was designed to gain insight into PB and TURSO effects on mechanistic targets of engagement and disease biology in AD. The primary clinical efficacy outcome was a global statistical test combining three endpoints relevant to disease trajectory (cognition [Mild/Moderate Alzheimer's Disease Composite Score], function [Functional Activities Questionnaire], and total hippocampal volume on magnetic resonance imaging). Secondary clinical outcomes included various cognitive, functional, and neuropsychiatric assessments. Cerebrospinal fluid (CSF) biomarkers spanning multiple pathophysiological pathways in AD were evaluated in participants with both baseline and Week 24 samples (exploratory outcome). RESULTS: PEGASUS enrolled 95 participants (intent-to-treat [ITT] cohort); cognitive assessments indicated significantly greater baseline cognitive impairment in the PB and TURSO (n = 51) versus placebo (n = 44) group. Clinical efficacy outcomes did not significantly differ between treatment groups in the ITT cohort. CSF interleukin-15 increased from baseline to Week 24 within the placebo group (n = 34). In the PB and TURSO group (n = 33), reductions were observed in core AD biomarkers phosphorylated tau-181 (p-tau181) and total tau; synaptic and neuronal degeneration biomarkers neurogranin and fatty acid binding protein-3 (FABP3); and gliosis biomarker chitinase 3-like protein 1 (YKL-40), while the oxidative stress marker 8-hydroxy-2-deoxyguanosine (8-OHdG) increased. Between-group differences were observed for the Aß42/40 ratio, p-tau181, total tau, neurogranin, FABP3, YKL-40, interleukin-15, and 8-OHdG. Additional neurodegeneration, inflammation, and metabolic biomarkers showed no differences between groups. DISCUSSION: While between-group differences in clinical outcomes were not observed, most likely due to the small sample size and relatively short treatment duration, exploratory biomarker analyses suggested that PB and TURSO engages multiple pathophysiologic pathways in AD. Highlights: Proteostasis and mitochondrial stress play key roles in Alzheimer's disease (AD).Sodium phenylbutyrate and taurursodiol (PB and TURSO) targets these mechanisms.The PEGASUS trial was designed to assess PB and TURSO effects on biologic AD targets.PB and TURSO reduced exploratory biomarkers of AD and neurodegeneration.Supports further clinical development of PB and TURSO in neurodegenerative diseases.

Effects of PB-TURSO on the transcriptional and metabolic landscape of sporadic ALS fibroblasts.

OBJECTIVE: 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. Therefore, our goal was to obtain an unbiased landscape of the molecular effects of AMX0035 in ALS patient-derived cells. METHODS: We investigated the transcriptomic and metabolomic profiles of primary skin fibroblasts from sporadic ALS patients and healthy controls (n = 12/group) treated with PB, TUDCA, or PB-TUDCA combination (Combo). Data were evaluated with multiple approaches including differential gene expression and metabolite abundance, Gene Ontology and metabolic pathway analysis, weighted gene co-expression correlation analysis (WGCNA), and combined multiomics integrated analysis. RESULTS: 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 nucleocytoplasmic transport, unfolded protein response, mitochondrial function, RNA metabolism, and innate immunity. WGCNA showed significant correlations between ALS gene expression modules and clinical parameters that were abolished by Combo treatment. INTERPRETATION: 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 with the individual compounds and provides clues to drug targets and mechanisms of action, which may underlie the benefits of this investigational drug combination.

Multidimensional analysis and therapeutic development using patient iPSC-derived disease models of Wolfram syndrome.

Wolfram syndrome is a rare genetic disorder largely caused by pathogenic variants in the WFS1 gene and manifested by diabetes mellitus, optic nerve atrophy, and progressive neurodegeneration. Recent genetic and clinical findings have revealed Wolfram syndrome as a spectrum disorder. Therefore, a genotype-phenotype correlation analysis is needed for diagnosis and therapeutic development. Here, we focus on the WFS1 c.1672C>T, p.R558C variant, which is highly prevalent in the Ashkenazi Jewish population. Clinical investigation indicated that patients carrying the homozygous WFS1 c.1672C>T, p.R558C variant showed mild forms of Wolfram syndrome phenotypes. Expression of WFS1 p.R558C was more stable compared with the other known recessive pathogenic variants associated with Wolfram syndrome. Human induced pluripotent stem cell-derived (iPSC-derived) islets (SC-islets) homozygous for WFS1 c.1672C>T variant recapitulated genotype-related Wolfram syndrome phenotypes. Enhancing residual WFS1 function through a combination treatment of chemical chaperones mitigated detrimental effects caused by the WFS1 c.1672C>T, p.R558C variant and increased insulin secretion in SC-islets. Thus, the WFS1 c.1672C>T, p.R558C variant causes a mild form of Wolfram syndrome phenotypes, which can be remitted with a combination treatment of chemical chaperones. We demonstrate that our patient iPSC-derived disease model provides a valuable platform for further genotype-phenotype analysis and therapeutic development for Wolfram syndrome.