# Novel Treatments for PXE

> **NIH NIH R01** · THOMAS JEFFERSON UNIVERSITY · 2021 · $330,393

## Abstract

ABSTRACT
This application focuses on pseudoxanthoma elasticum (PXE), a prototype of heritable ectopic mineralization
disorders. PXE is caused by mutations in the ABCC6 gene which encodes ABCC6, an efflux transporter
expressed primarily in the liver. Characteristic clinical manifestations include cutaneous findings which signify
the potential for development of ocular complications leading to loss of visual acuity and blindness, as well as
cardiovascular involvement, including nephrogenic hypertension, intermittent claudication, bleeding from
gastrointestinal arteries, early myocardial infarct and stroke. There is no specific or effective treatment for PXE
or related ectopic mineralization disorders. Significant recent progress has been made in understanding the
pathomechanistic details resulting in ectopic mineralization in PXE, and this information has now provided a
platform to develop novel treatments. A particularly intriguing recent observation made by us is that release of
ATP from hepatocytes to the circulation is dependent on functional ABCC6, and in the absence of ABCC6
activity, as in PXE, the plasma PPi levels are markedly reduced. Since PPi is a powerful anti-mineralization
factor, reduced plasma PPi levels and particularly reduced PPi/Pi ratio allow ectopic mineralization in the
peripheral tissues to ensue. In this study, we will test the unifying hypothesis that restoration of plasma PPi
levels in patients with PXE will counteract the clinical manifestations of this devastating disease. To enhance
plasma PPi levels, we have developed three Specific Aims proposing (a) pharmacologically enhanced release
of cellular ATP either in an ABCC6-dependent or ABCC6-independent manner; (b) inhibition of tissue non-
specific alkaline phosphatase (TNAP), the enzyme responsible for degradation of plasma PPi to Pi; and (c) oral
administration of PPi with subsequent increases in plasma PPi levels. These plans are based on solid
preliminary data, and they take advantage of well-characterized mouse and rat models developed and
characterized in our laboratory, recapitulating clinical, histopathologic, ultrastructural and genetic features of
PXE. Our plans also include a Phase I Clinical Trial to demonstrate the absorption of orally administered PPi in
human volunteers and in patients with PXE with assay of pharmacokinetics in plasma.
 Collectively, our state-of-the-art studies utilizing in vivo model systems for PXE are expected to provide
critical preclinical information of potential efficacy to restore plasma PPi levels in PXE, with subsequent
inhibition of ectopic mineralization. Such information is reasonably expected to be useful towards development
of pharmacologic treatments for PXE, as well as for other ectopic mineralization disorders, for which no
effective or specific therapy is currently available.

## Key facts

- **NIH application ID:** 10162503
- **Project number:** 5R01AR072695-04
- **Recipient organization:** THOMAS JEFFERSON UNIVERSITY
- **Principal Investigator:** Qiaoli Li
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $330,393
- **Award type:** 5
- **Project period:** 2018-05-07 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10162503

## Citation

> US National Institutes of Health, RePORTER application 10162503, Novel Treatments for PXE (5R01AR072695-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10162503. Licensed CC0.

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