Odevixibat: a promising new treatment for progressive familial intrahepatic cholestasis.

INTRODUCTION: Progressive familial intrahepatic cholestasis (PFIC) refers to a group of heterogeneous, mostly autosomal recessive disorders resulting from the inability to properly form and excrete bile from hepatocytes. The resulting shared phenotype is one of hepatocellular cholestasis. Clinical management targeting refractory itch and surgical interventions to interrupt the enterohepatic circulation are often pursued with variable efficacy. Recent development of the family of IBAT inhibitor therapeutics has introduced a novel tool in the armamentarium for the treatment of PFIC. AREAS COVERED: Data from Phase 3 and 3 clinical trials were reviewed. The primary endpoints in most studies included effect on pruritus, serum bile acid levels, and quality of life metrics, with the duration of the study ranging between 24 and 72 weeks. Most common adverse events included diarrhea, vomiting, and elevation in transaminases. EXPERT OPINION: IBAT inhibition with therapeutics such as odevibixat have shown that it is well-tolerated and efficacious in mitigating itch and reducing serum bile acid levels. While the few early published trials with odevixibat have shown good efficacy, what remains to be seen is long-term, sustainable improvement and if or how these medications will supplement or replace the current medical and surgical therapies available for managing PFIC disorders.

Impaired estrogen signaling underlies regulatory T cell loss-of-function in the chronically inflamed intestine.

Signaling of 17ß-estradiol (estrogen) through its two nuclear receptors, α and ß (ERα, ERß), is an important mechanism of transcriptional regulation. Although ERs are broadly expressed by cells of the immune system, the mechanisms by which they modulate immune responses remain poorly understood. ERß-specific signaling is reduced in patients with chronic inflammatory diseases, including systemic lupus erythematosus and inflammatory bowel disease, and our previous work suggests that dysregulation of ERß-specific signaling contributes to enhanced intestinal inflammation in female SAMP/YitFC mice, a spontaneous model of Crohn's disease-like ileitis. The present study builds on these prior observations to identify a nonredundant, immunoprotective role for ERß-specific signaling in TGF-ß-dependent regulatory T cell (Treg) differentiation. Using a strain of congenic SAMP mice engineered to lack global expression of ERß, we observed dramatic, female-specific exacerbation of intestinal inflammation accompanied by significant reductions in intestinal Treg frequency and function. Impaired Treg suppression in the absence of ERß was associated with aberrant overexpression of Tsc22d3 (GILZ), a glucocorticoid-responsive transcription factor not normally expressed in mature Tregs, and ex vivo data reveal that forced overexpression of GILZ in mature Tregs inhibits their suppressive function. Collectively, our findings identify a pathway of estrogen-mediated immune regulation in the intestine, whereby homeostatic expression of ERß normally functions to limit Treg-specific expression of GILZ, thereby maintaining effective immune suppression. Our data suggest that transcriptional cross-talk between glucocorticoid and steroid sex hormone signaling represents an important and understudied regulatory node in chronic inflammatory disease.

A rapid, automated surface protein profiling of single circulating exosomes in human blood.

Circulating exosomes provide a promising approach to assess novel and dynamic biomarkers in human disease, due to their stability, accessibility and representation of molecules from source cells. However, this potential has been stymied by lack of approaches for molecular profiling of individual exosomes, which have a diameter of 30-150 nm. Here we report a rapid analysis approach to evaluate heterogeneous surface protein expression in single circulating exosomes from human blood. Our studies show a differential CD47 expression in blood-derived individual circulating exosomes that is correlated with breast cancer status, demonstrating a great potential of individual exosome profiles in biomarker discovery. The sensitive and high throughput platform of single exosome analysis can also be applied to characterizing exosomes derived from other patient fluids.