Comparison of wild-type and high-risk PNPLA3 variants in a human biomimetic liver microphysiology system for metabolic dysfunction-associated steatotic liver disease precision therapy.

Autor:	Xia M; Drug Discovery Institute, University of Pittsburgh, Pittsburgh, PA, United States., Varmazyad M; Drug Discovery Institute, University of Pittsburgh, Pittsburgh, PA, United States., Pla-Palacín I; Drug Discovery Institute, University of Pittsburgh, Pittsburgh, PA, United States., Gavlock DC; Drug Discovery Institute, University of Pittsburgh, Pittsburgh, PA, United States., DeBiasio R; Drug Discovery Institute, University of Pittsburgh, Pittsburgh, PA, United States., LaRocca G; Drug Discovery Institute, University of Pittsburgh, Pittsburgh, PA, United States., Reese C; Drug Discovery Institute, University of Pittsburgh, Pittsburgh, PA, United States., Florentino RM; Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, United States.; Center for Transcriptional Medicine, University of Pittsburgh, Pittsburgh, PA, United States.; Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA, United States., Faccioli LAP; Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, United States.; Center for Transcriptional Medicine, University of Pittsburgh, Pittsburgh, PA, United States.; Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA, United States., Brown JA; Drug Discovery Institute, University of Pittsburgh, Pittsburgh, PA, United States.; Department of Computational and System Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, United States., Vernetti LA; Drug Discovery Institute, University of Pittsburgh, Pittsburgh, PA, United States.; Department of Computational and System Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, United States., Schurdak M; Drug Discovery Institute, University of Pittsburgh, Pittsburgh, PA, United States.; Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA, United States.; Department of Computational and System Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, United States., Stern AM; Drug Discovery Institute, University of Pittsburgh, Pittsburgh, PA, United States.; Department of Computational and System Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, United States., Gough A; Drug Discovery Institute, University of Pittsburgh, Pittsburgh, PA, United States.; Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA, United States., Behari J; Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA, United States.; Division of Gastroenterology, Hepatology and Nutrition, School of Medicine, University of Pittsburgh, Pittsburgh, PA, United States., Soto-Gutierrez A; Drug Discovery Institute, University of Pittsburgh, Pittsburgh, PA, United States.; Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, United States.; Center for Transcriptional Medicine, University of Pittsburgh, Pittsburgh, PA, United States.; Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA, United States., Taylor DL; Drug Discovery Institute, University of Pittsburgh, Pittsburgh, PA, United States.; Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA, United States.; Department of Computational and System Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, United States., Miedel MT; Drug Discovery Institute, University of Pittsburgh, Pittsburgh, PA, United States.; Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, United States.; Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA, United States.
Jazyk:	angličtina
Zdroj:	Frontiers in cell and developmental biology [Front Cell Dev Biol] 2024 Sep 11; Vol. 12, pp. 1423936. Date of Electronic Publication: 2024 Sep 11 (Print Publication: 2024).
DOI:	10.3389/fcell.2024.1423936
Abstrakt:	Metabolic dysfunction-associated steatotic liver disease (MASLD) is a worldwide health epidemic with a global occurrence of approximately 30%. The pathogenesis of MASLD is a complex, multisystem disorder driven by multiple factors, including genetics, lifestyle, and the environment. Patient heterogeneity presents challenges in developing MASLD therapeutics, creating patient cohorts for clinical trials, and optimizing therapeutic strategies for specific patient cohorts. Implementing pre-clinical experimental models for drug development creates a significant challenge as simple in vitro systems and animal models do not fully recapitulate critical steps in the pathogenesis and the complexity of MASLD progression. To address this, we implemented a precision medicine strategy that couples the use of our liver acinus microphysiology system (LAMPS) constructed with patient-derived primary cells. We investigated the MASLD-associated genetic variant patatin-like phospholipase domain-containing protein 3 (PNPLA3) rs738409 (I148M variant) in primary hepatocytes as it is associated with MASLD progression. We constructed the LAMPS with genotyped wild-type and variant PNPLA3 hepatocytes, together with key non-parenchymal cells, and quantified the reproducibility of the model. We altered media components to mimic blood chemistries, including insulin, glucose, free fatty acids, and immune-activating molecules to reflect normal fasting (NF), early metabolic syndrome (EMS), and late metabolic syndrome (LMS) conditions. Finally, we investigated the response to treatment with resmetirom, an approved drug for metabolic syndrome-associated steatohepatitis (MASH), the progressive form of MASLD. This study, using primary cells, serves as a benchmark for studies using "patient biomimetic twins" constructed with patient induced pluripotent stem cell (iPSC)-derived liver cells using a panel of reproducible metrics. We observed increased steatosis, immune activation, stellate cell activation, and secretion of pro-fibrotic markers in the PNPLA3 GG variant compared to the wild-type CC LAMPS, consistent with the clinical characterization of this variant. We also observed greater resmetirom efficacy in the PNPLA3 wild-type CC LAMPS compared to the GG variant in multiple MASLD metrics, including steatosis, stellate cell activation, and the secretion of pro-fibrotic markers. In conclusion, our study demonstrates the capability of the LAMPS platform for the development of MASLD precision therapeutics, enrichment of patient cohorts for clinical trials, and optimization of therapeutic strategies for patient subgroups with different clinical traits and disease stages. Competing Interests: DT, AG, and MS have equity in Nortis, a company supplying MPS chips/some automation, and Eve AnalyticsTM, analyzing and computationally modeling data on patient-derived microphysiology systems. JB received research grant funding from Gilead, Pfizer, AstraZeneca, and ENDRA Life Sciences. His institution has had research contracts with Intercept, Pfizer, Galectin, Exact Sciences, Inventiva, Enanta, Shire, Gilead, Allergan, Celgene, Galmed, Genentech, Rhythm Pharmaceuticals, and Madrigal. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2024 Xia, Varmazyad, Pla-Palacín, Gavlock, DeBiasio, LaRocca, Reese, Florentino, Faccioli, Brown, Vernetti, Schurdak, Stern, Gough, Behari, Soto-Gutierrez, Taylor and Miedel.)
Databáze:	MEDLINE
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