Prognostic liver signature profiles in biopsy tissues from non-alcoholic fatty liver disease patients followed for fibrosis progression

ABSTRACT: Background/Aims: There is a major unmet need to assess prognostic impact of anti-fibrotics in clinical trials due to the slow rate of liver fibrosis progression. We aimed to develop a surrogate biomarker to predict future fibrosis progression. Methods: A Fibrosis Progression Signature (FPS) was defined to predict fibrosis progression within 5 years in HCV and NAFLD patients with no to minimal fibrosis at baseline (n=421), and validated in an independent NAFLD cohort (n=78). The FPS was used to assess response to 13 candidate anti-fibrotics in organotypic ex vivo cultures of clinical fibrotic liver tissues (n=78), and cenicriviroc in NASH patients enrolled in a clinical trial (n=19, NCT02217475). A serum-protein-based surrogate FPS (FPSec) was developed and technically evaluated in a liver disease patient cohort (n=79). Results: A 20-gene FPS was defined and validated in an independent NAFLD cohort (aOR=10.93, AUROC=0.86). Among computationally inferred fibrosis-driving FPS genes, BCL2 was confirmed as a potential pharmacological target using clinical liver tissues. Systematic ex vivo evaluation of 13 candidate anti-fibrotics identified rational combination therapies based on epigallocatechin gallate, some of which were validated for enhanced anti-fibrotic effect in ex vivo culture of clinical liver tissues. In NASH patients treated with cenicriviroc, FPS modulation was associated with 1-year fibrosis improvement accompanied by suppression of the E2F pathway. Induction of PPAR-alfa pathway was absent in patients without fibrosis improvement, suggesting benefit of combining PPAR-alfa agonism to improve anti-fibrotic efficacy of cenicriviroc. A 7-protein FPSec panel showed concordant prognostic prediction with FPS. Conclusion: FPS predicts long-term fibrosis progression in an etiology-agnostic manner, which can inform anti-fibrotic drug development.

ORGANISM(S): Homo sapiens

PROVIDER: GSE182060 | GEO | 2021/12/22

REPOSITORIES: GEO