# Beta-catenin inhibition as a novel therapeutic strategy for porphyria

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $462,077

## Abstract

The porphyrias are a group of metabolic disorders that are caused by defects in heme biosynthesis pathway
enzymes, and liver is commonly either a source or target of excess porphyrins. Treatment for most of the
porphyrias is limited, and often focused on symptomatic relief and palliative care. Thus, mechanistic-based
studies that emphasize therapeutic development are desperately needed. Previous work has identified the
Wnt/b-catenin signaling pathway as a modulatable target in the 3,5-diethoxycarbonyl-1,4-dihydrocollidine
(DDC) diet-induced mouse model of porphyria. Inhibition of b-catenin in mice subjected to DDC results in a
significant reduction in liver injury due to decreased porphyrin accumulation. We identified a network of key
heme biosynthesis enzymes such as δ-aminolevulinic acid (ALA) synthetase and ALA-dehydratase that are
suppressed in the absence of b-catenin, resulting in decreased production of porphyrin intermediates and
DDC-associated protein aggregation. Autophagy is also increased in mice lacking b-catenin, which may further
contribute to protection from injury. Thus, the overarching hypothesis of the proposal is that inhibiting
Wnt/b-catenin signaling in clinically-relevant models of porphyria will alleviate injury and progression of
disease through decreased production of porphyrin intermediates and/or increased autophagy. In aim 1, we
will determine the most proximal step in the pathway that is affected by b-catenin inhibition by treating
hepatocytes with ALA and measuring the appearance of porphyrin intermediates; investigate the mechanism
by which b-catenin regulates heme enzymes through site-directed mutagenesis, in silico studies, and chromatin
immunoprecipitation; and demonstrate therapeutic relevance of targeting β-catenin in patients by utilizing
immunohistochemistry to correlate the extent of b-catenin expression with expression of heme enzymes. In
aim 2, we will characterize the role and regulation of autophagy in porphyria after Wnt/b-catenin inhibition.
We will use RFP-EGFP-LC3 mice, a pH-dependent fluorescent reporter strain, and a genetic knockout of
glutamine synthetase, a component of the b-catenin/mTOR pathway, as well as in vitro assays, to
comprehensively address the contribution of this cellular process to the observed protected phenotype. In aim
3, we will determine whether inhibiting b-catenin in genetic mouse models of porphyria decreases porphyrin
accumulation and improves liver pathology. Two well-characterized porphyria models: the ferrochelatase
(Fechm1Pas) mutant mice, which mimics human erythropoietic protoporphyria with significant liver
involvement; and the T1/T2 mouse, which is compound heterozygous for hydroxymethylbilane synthase and
mimics acute intermittent porphyria upon stimulation with phenobarbitol, will be utilized to determine
whether therapeutic intervention with a b-catenin inhibitor can prevent progression or provide protection
during acute attacks. Thus, the proposed studies will...

## Key facts

- **NIH application ID:** 10119767
- **Project number:** 1R01DK124412-01A1
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Kari N Nejak-Bowen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $462,077
- **Award type:** 1
- **Project period:** 2020-09-15 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10119767

## Citation

> US National Institutes of Health, RePORTER application 10119767, Beta-catenin inhibition as a novel therapeutic strategy for porphyria (1R01DK124412-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10119767. Licensed CC0.

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