# New Therapies for Liver Fibrosis and Hyperproliferation in Alpha1-AT Deficiency

> **NIH NIH P01** · WASHINGTON UNIVERSITY · 2020 · $1,925,515

## Abstract

Project Summary
This program project will discover and test novel compounds as potential therapeutic agents, as well as test
and discover signaling pathways as potential modifiers, of liver disease due to α1antitrypsin deficiency (ATD),
one of the most common genetic causes of liver disease and a frequent indication for liver transplantation.
The program project grew out 4 collaborations: collaboration between Drs Perlmutter and Silverman showed
that, by enhancing autophagic degradation of mutant ATZ, carbamazepine and phenothiazines could reduce
hepatic ATZ load and fibrosis in the PiZ mouse model of ATD, and therein provided evidence that endogenous
proteostasis mechanisms could be targeted for therapeutics; collaboration between Drs Silverman and
Perlmutter using a newly developed C. elegans model of ATD and a high-content screening platform generated
a powerful engine for discovery of additional drugs and modifiers; collaboration between Drs Bahar, Silverman
and Perlmutter has added computational pharmacological strategies to potential drug discovery for ATD;
collaboration between Dr. Fox and Perlmutter has shown that transplanted hepatocytes will re-populate the liver
of the PiZ mouse model of ATD and that iPS-derived hepatocytes (iHeps)can model personalized variations in
the liver disease phenotype of ATD, providing the basis for use of iHeps for `humanized' mouse models of ATD
with the ultimate goal of personalized medicine for ATD. The 3 projects include: 1) testing of novel drug and
genetic modifier candidates in mammalian cell line and mouse models of ATD (PI-Perlmutter); 2) use of the C.
elegans model of ATD to discover new drugs and modifiers (PI-Silverman); 3) repopulation studies using a new
immune- deficient PiZ mouse model and iPS cell lines to develop `humanized' mice that model ATD together
with host-specific modifiers (PI: Fox). The 3 cores include: A) Cell and Tissue Imaging (PI- Fitzpatrick); B)
Computational Pharmacology (PI-Bahar); C) Genome Engineering (PI-Milbrandt). This outstanding group of
investigators will use existing and develop novel model systems which together with sophisticated drug
discovery tools, pathologic and genomic techniques will lead to new drugs and druggable targets for ATD.

## Key facts

- **NIH application ID:** 9994902
- **Project number:** 5P01DK096990-07
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** David H Perlmutter
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $1,925,515
- **Award type:** 5
- **Project period:** 2012-09-24 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9994902

## Citation

> US National Institutes of Health, RePORTER application 9994902, New Therapies for Liver Fibrosis and Hyperproliferation in Alpha1-AT Deficiency (5P01DK096990-07). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9994902. Licensed CC0.

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