# A vascularized patient-derived iPSC liver acinus microphysiology system as an innovative precision medicine platform for optimizing clinical trial design for nonalcoholic fatty liver disease

> **NIH NIH UG3** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $748,638

## Abstract

A vascularized patient-derived iPSC liver acinus microphysiology system (vLAMPS) is an
innovative precision medicine platform for optimizing clinical trial design for nonalcoholic fatty
liver disease (NAFLD). Non-alcoholic fatty liver disease (NAFLD) is a major health crisis with no
approved therapeutics and many failures in the clinic. The prevalence of NAFLD is estimated to
increase from 25% of the US population in 2015 (~83 million) to over 100 million by 2030,
accompanied by an increase in nonalcoholic steatohepatitis (NASH), the progressive form of the
disease, that can lead to cirrhosis with liver failure and hepatocellular carcinoma (HCC). Despite
its public health importance, there is currently no FDA-approved therapy for any stage of
NAFLD. NAFLD/NASH is a complex heterogeneous disorder involving multiple molecular
pathways. Development of efficacious pharmacotherapy has been hampered by the limited
utility of preclinical drug testing models. Simple cell culture and animal models do not
recapitulate the spectrum of NASH phenotypes in humans. Highlighting these species
differences, knock-in murine models with the high-risk NASH-associated genetic polymorphism,
PNPLA3 I148M, develop hepatic steatosis but do not recapitulate the progressive disease seen
in humans. Additionally, heterogeneity in risk of progression of NASH, individual genetic
variations modulating risk of fibrosis progression, and presence of NAFLD-associated metabolic
comorbidities such as Type 2 diabetes mellitus (T2DM), adds additional complexity. We will
implement the vLAMPS to initially characterize both a “normal” and a NAFLD/NASH vLAMPS
generated from primary human liver cells (hepatocytes, liver sinusoidal endothelial cells, stellate
and Kupffer cells) and then reproduce the results with induced pluripotent stem cells (iPSCs).
We will ultimately generate patient-specific iPSCs of the four cell types from patients in our
NAFLD clinic to create patient-specific vLAMPS. We will test two cohorts: 1) patients with the
PNPLA3 I 148M variant and 2) patients with the wild-type PNPLA3 to identify the patients who
respond to two NAFLD drugs that have or are now going through clinical trials and two control
drugs. Importantly, this paradigm circumvents the conundrum of high-risk patients being
enrolled in large prolonged studies with a high likelihood of failure being simultaneously
disqualified from other potentially beneficial studies/treatments. This approach will prove
transformational for clinical trial design by enriching for subjects most likely to benefit from a
therapy, and in the future, after more than one currently investigational drugs are approved, for
precision medicine to identify the most efficacious therapy for high-risk subgroups.

## Key facts

- **NIH application ID:** 10033652
- **Project number:** 1UG3TR003289-01
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Jaideep Behari
- **Activity code:** UG3 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $748,638
- **Award type:** 1
- **Project period:** 2020-07-15 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10033652

## Citation

> US National Institutes of Health, RePORTER application 10033652, A vascularized patient-derived iPSC liver acinus microphysiology system as an innovative precision medicine platform for optimizing clinical trial design for nonalcoholic fatty liver disease (1UG3TR003289-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10033652. Licensed CC0.

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