# Enzyme Therapy for PXE: Breaking the Barrier of Ectopic Calcification

> **NIH NIH R21** · THOMAS JEFFERSON UNIVERSITY · 2022 · $187,462

## Abstract

ABSTRACT
Pseudoxanthoma elasticum (PXE) is a genetic disorder of ectopic calcification with considerable morbidity and
mortality due to deposition of hydroxyapatite crystals in the connective tissues. Though ABCC6 was identified
as the causative gene for PXE 20 years ago, the disease mechanism was just recently unveiled and there is
currently still no effective or specific treatment for the pathologic calcification. We have previously developed and
characterized mouse models for PXE, and these mice provide the platform for preclinical development of
therapeutics for this currently intractable condition. A critical pathological characteristic in PXE is the reduction
in circulating levels of inorganic pyrophosphate (PPi), a key endogenous inhibitor of calcification. Therefore, the
goal of the research we propose herein is to use our mouse models in preclinical studies to develop safe and
effective treatments that can prevent ectopic calcification in PXE by normalization of extracellular PPi levels.
 We have identified ENPP1 and TNAP proteins as key regulators of PPi homeostasis. ENPP1 and TNAP
have opposing actions in maintaining extracellular PPi concentrations, the former generating PPi and the latter
hydrolyzing PPi. We have generated a recombinant ENPP1 enzyme biologic and our strong preliminary data
demonstrate that this therapeutic biologic raised plasma PPi levels in a mouse model of PXE, and its circulating
half-life can be extended by pharmacologic inhibition of TNAP. Based upon these findings and the known
enzymatic activities of ENPP1 and TNAP, we propose that modulation of plasma PPi, either using a recombinant
ENPP1 enzyme, TNAP inhibitors, or a combination of both approaches, represents an innovative strategy to
prevent the ectopic calcification that arises as a consequence of PPi deficiency. To test this hypothesis, we
propose to utilize genetic and pharmacologic approaches to define mechanisms by which inhibition of TNAP
extends the plasma half-life of PPi from ENPP1 enzyme supplementation, and subsequently prevents and/or
diminishes the ectopic calcification in a mouse model of PXE. Our team has the requisite research expertise in
the ENPP1-PPi-TNAP axis and appropriate mouse models to complete these studies.
 Collectively, we anticipate that the proposed studies will provide critical translational information from
preclinical approaches that will allow development of novel treatments for ectopic calcification in patients with
PXE. If successful, our findings will advance clinical management of ectopic calcification broadly, as PPi
deficiency plays an important role in development of ectopic calcification in other genetic and acquired disorders.

## Key facts

- **NIH application ID:** 10527964
- **Project number:** 1R21AR080277-01A1
- **Recipient organization:** THOMAS JEFFERSON UNIVERSITY
- **Principal Investigator:** Qiaoli Li
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $187,462
- **Award type:** 1
- **Project period:** 2022-08-25 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10527964

## Citation

> US National Institutes of Health, RePORTER application 10527964, Enzyme Therapy for PXE: Breaking the Barrier of Ectopic Calcification (1R21AR080277-01A1). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10527964. Licensed CC0.

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