# Combination therapy using siRNA nanocompelex and PD-L1 inhibitor for alcoholic liver fibrosis

> **NIH NIH R01** · UNIVERSITY OF MISSOURI KANSAS CITY · 2022 · $349,444

## Abstract

Project Summary
 Liver fibrosis is a wound healing process characterized by the accumulation of excess extracellular
matrix (ECM) in the liver. Alcohol abuse is one of the most common causes of liver fibrosis/cirrhosis in
western developed countries, accounting for more than 50% of cirrhosis cases. If left untreated, liver
fibrosis will develop into liver cirrhosis, which is irreversible and affects nearly 633,233 adults in the
United States. Unfortunately, there is no standard treatment for liver fibrosis till now. Therefore,
effective antifibrotic medicines are needed urgently
 The accumulation of type I collagen in fibrotic liver is primarily due to an increase in the half-life of
its mRNA in activated hepatic stellate cells (HSCs). We recently demonstrated that blocking PCBP2
expression using siRNA can efficiently decrease the stability of the collagen α1(I) mRNA and
subsequently reverse alcohol- and cytokine-induced fibrogenesis in HSCs. We also discovered an
IGF2R-specific peptide that can be used to specifically deliver cargos to activated HSCs. We will
improve our current nanocomplex system to enhance the delivery of the PCBP2 siRNA to activated
HSCs.
 It has been well established that the activation and proliferation of HSCs is the central event in liver
fibrogenesis. Recently, experimental and clinical studies have shown that inducing apoptosis of
activated HSCs in fibrotic liver is a rational and potential anti-fibrotic approach. It was found that HSCs
inhibit T cells and B cells through PD-L1 on the surface of HSCs. PD-L1 is overexpressed in activated
HSCs, leading to the strong immune modulatory activity of the activated HSCs against T-cell response.
Activated HSCs exert inhibitory effects on infiltrating CD8+ T cells and induction effects on CD4+CD25+
regulatory T (Treg) cells. The immune modulatory activity of activated HSCs can be reversed by anti-
PD-L1 antibodies to block the PD-1/PD-L1 interaction. We therefore hypothesize that anti-PD-L1
inhibitor can be utilized to restore the activity of infiltrating T cells in the fibrotic liver to clear activated
HSCs which overexpress PD-L1.
 Our strategy is to develop a combination therapy to reverse the accumulated type I collagen using
PCBP2 siRNAs and induce apoptosis of activated HSCs using PD-L1 inhibitors. Our central hypothesis
is that alcoholic liver fibrosis can be reversed by targeting two different key steps in liver fibrogenesis.

## Key facts

- **NIH application ID:** 10439677
- **Project number:** 5R01AA021510-10
- **Recipient organization:** UNIVERSITY OF MISSOURI KANSAS CITY
- **Principal Investigator:** Kun Cheng
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $349,444
- **Award type:** 5
- **Project period:** 2012-09-15 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10439677

## Citation

> US National Institutes of Health, RePORTER application 10439677, Combination therapy using siRNA nanocompelex and PD-L1 inhibitor for alcoholic liver fibrosis (5R01AA021510-10). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10439677. Licensed CC0.

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