# Novel therapies that target mitochondrial dysfunction for treatment of a1-antitrypsin deficiency liver disease

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2024 · $584,605

## Abstract

PROJECT SUMMARY:
 α1-antitrypsin deficiency (ATD) liver disease is one of the most common genetic causes of liver disease
in children and adults. The only currently available treatment is liver transplantation. The pathobiology of the
liver disease begins with a point mutation in α1-antitrypsin (AT), one of the most abundant secretory
glycoproteins of the liver. The variant, α1-antitrypsin Z (ATZ), is prone to misfolding and that leads to its
accumulation within the early part of the secretory pathway of liver cells. Most of the ATZ accumulates in the
endoplasmic reticulum (ER) as polymers and aggregates, and we now know that it is this accumulation of
polymerogenic, aggregation-prone ATZ that initiates the process of liver damage by a gain-of-toxic function
mechanism. Very little is known about the pathobiological steps after accumulation of ATZ that result in liver
damage but it is assumed that liver cell function becomes impaired with stereotypical fibrogenic consequences.
Marked alterations of mitochondria have been observed in liver cells of human ATD patients and the PiZ
mouse model of ATD, leading to speculation that mitochondrial dysfunction is at least part of the final steps in
the demise of liver cell function that characterizes severe ATD liver disease.
 Over the years we have learned that only a sub-group of homozygotes for ATZ develop progressive
liver disease and the majority completely escape clinical effects. This observation has led to the recognition
that genetic and environmental modifiers play an important role in the pathobiological effects of ATZ. Work led
by the Perlmutter laboratory has shown that the intracellular degradation pathway known as autophagy is a key
determinant of ATZ accumulation in liver cells and that drugs which enhance the autophagic degradation of
ATZ decrease hepatic fibrosis in animal models, including the ATZ nematode and PiZ mouse models. Other
recent studies have shown specificity for the molecular pathways involved in autophagy of specific organelles,
and the term `ER-phagy' has recently been recognized as at least part of the process by which ATZ is
specifically degraded. Furthermore, a very important new study has shown that at least one ER-phagy pathway
is regulated by oxidative phosphorylation genes and mitochondrial function.
 Based on these considerations and new preliminary data described in the proposal, we now believe
that mitochondrial impairment is a key part of the pathobiology of ATD liver disease in two ways, impaired liver
cell energy metabolism and reduced autophagic response, and, therein, that mitochondrial function is a very
appealing target for potential therapeutic interventions. In this grant we propose to investigate the effects of
ATZ accumulation on mitochondrial function to better understand the mechanism by which liver is damaged
and to investigate whether mitochondrial function can be targeted for therapy.
 Our overarching goal with these studies is to provide a basis f...

## Key facts

- **NIH application ID:** 10747370
- **Project number:** 5R01DK131215-03
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** David H Perlmutter
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $584,605
- **Award type:** 5
- **Project period:** 2021-12-16 → 2025-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10747370

## Citation

> US National Institutes of Health, RePORTER application 10747370, Novel therapies that target mitochondrial dysfunction for treatment of a1-antitrypsin deficiency liver disease (5R01DK131215-03). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10747370. Licensed CC0.

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