Novel Treatments for PXE

摘要

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.