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

> **NIH NIH R01** · UNIVERSITY OF MISSOURI KANSAS CITY · 2021 · $338,729

## Abstract

Alzheimer’s disease (AD) is a devastating age-related neurodegenerative disorder that affects 5.6
million Americans age 65 and older. The number of Americans age 65 and older with AD is projected to
reach 13.8 million by 2050. Although the Food and Drug Administration (FDA) has approved five drugs
for AD, no one of them can slow or stop the damage and destruction of neurons that causing the
symptoms of AD. Therefore, there is an urgent need to better understand AD and develop novel therapies.
It is generally believed that alcohol consumption affects the risk of AD. However, the association
between alcohol and AD is very complex, and the conclusions are still controversial. As a result, more
investigations into the association between alcohol and AD are highly needed.
The brain was traditionally considered immune-privileged because of the blood-brain barrier (BBB)
and the lack of lymphatic vessels in the brain. However, recent studies have generated compelling data
to revise this concept. The brain is not completely immune-privileged but is immunocompetent.
Particularly, the PD-1/PD-L1 pathway has attracted much attention in neurodegenerative diseases,
including AD and ALS. Both anti-PD-1 and anti-PD-L1 monoclonal antibodies have shown effectiveness
in reversing cognitive impairments and reducing disease pathology in a transgenic mouse model of AD
and a tau-driven disease model. The blockade of the PD-1/PD-L1 pathway is believed to restore the
immunological communication between the immune system and the brain. Nevertheless, the function
of PD-1/PD-L1 in the pathology of AD is not fully understood. Moreover, the anti-PD-1 or anti-Pd-L1
monoclonal antibodies cannot cross the BBB. It is, therefore, highly necessary to study whether small
anti-PD-L1 inhibitors, which may cross the BBB, have different effects than the antibodies.
 The objectives of the project are:1) Using an established rat alcoholism model to evaluate whether
alcohol consumption changes the immune cell profiles in the brain; 2) Investigate whether delivery of small
anti-PD-L1 inhibitors to the brain of 5XFAD transgenic mice can help combat AD.
 We have developed a rat alcoholism model to study alcoholic liver fibrosis in the parent grant. We will
use the same model to investigate the association between alcohol and immune cell profiles in the brain.
We have developed small anti-PD-L1 inhibitors that efficiently block the PD-L1/PD-1 interaction. Because
of their small size, they will have better chance to cross the BBB. We recently developed a BBB-
translocating peptide. We will conjugate this peptide to anti-PD-L1 inhibitors to increase their delivery to
the brain. Successful accomplishment of the project will provide more insights on how to combat AD by
regulating the immune cell profiles in the brain.

## Key facts

- **NIH application ID:** 10287867
- **Project number:** 3R01AA021510-09S1
- **Recipient organization:** UNIVERSITY OF MISSOURI KANSAS CITY
- **Principal Investigator:** Kun Cheng
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $338,729
- **Award type:** 3
- **Project period:** 2012-09-15 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10287867

## Citation

> US National Institutes of Health, RePORTER application 10287867, Combination therapy using siRNA nanocompelex and PD-L1 inhibitor for alcoholic liver fibrosis (3R01AA021510-09S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10287867. Licensed CC0.

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