History

Introduction

Patrick and Sharon Terry founded PXE International in 1995 to accelerate research that will result in the treatment of pseudoxanthoma elasticum. PXE International initiates, funds, and conducts research; provides support to affected families; and supports physicians.

• Initial Plan
• Groundwork
• Discovery of the Gene Associated with PXE
• Epidemiological Study
• Mutation Analysis
• Diagnostic Kit
• Cellular and Molecular Studies
• PXE Research Meeting
• Clinical Study at NIH
• Conclusion

Initial Plan

Pat was a fire sprinkler designer and Sharon was a former college chaplain when they learned in 1994 that their children (Elizabeth, born 12/12/87, and Ian, born 7/12/89) had PXE. Although they had no formal scientific background, they read medical literature, met with scientists and within two months crafted a comprehensive research plan (Figure 1).

Figure 1 - PXE Research Plan

The principles of the design are:

• Fast track all phases of research simultaneously in order to avoid bottlenecks
• Position the foundation as a firewall between patients and researchers to ensure maximum research participation
• Initiate, fund, conduct and coordinate research in a central role to maximize efficiency and speed
• Participate in the national genetics arena to leverage resources otherwise unavailable
• In all cases, effect change on a systems level so that all diseases benefit 

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Groundwork

The Terrys established PXE International as a 501 (c) (3). They enlisted Dr. Lionel Bercovitch of Brown University as medical director. Dr. Bercovitch is trained in both dermatology and ophthalmology and is selflessly dedicated to long hours of volunteer work for the foundation. A dedicated board and staff provide expertise and assistance.  Except for projects supported by grants from Yardi, the Helmsley Foundation and a few small family foundations over the years, all activities are funded through private donations  Our research meetings have an excellent track record of being funded by NIH grants.

During the first few years, PXE International:

• Assessed the state of PXE research, including a gap analysis and the funding of small projects in the gap as a way to gather enough data to apply for government and industry grants.
• Planned a cohesive strategy to avoid overlap and encourage innovative collaborative methods.
• Established a large registry (see Figure 2) to form the cohort needed for robust studies.
• Founded the PXE International BioBank, whose samples now number in the thousands. This lay-managed and -owned bank was the first of its kind in the world and is the model on which the Genetic Alliance BioBank is founded.

Figure 2

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Discovery of the Gene Associated with PXE

The PXE International Blood and Tissue Bank accelerated the discovery of the gene associated with PXE, and Patrick and Sharon Terry participated in the research. In addition to participating in actual wet bench work, they worked to coordinate the activities of a number of laboratories around the world. They were able to get two groups to cooperate, a rare event in the race to find a gene in the 1990's, and the two groups published articles in Nature Genetics. Sharon was a co-author of both articles. As a result of PXE International's material involvement in the discovery, Sharon Terry was listed as a co-inventor on the patent and then assigned her rights to PXE International. The patent issued in the United States in August 2004 and in Canada September 2009. It has been licensed to GeneDx for the diagnostic test.

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Epidemiological Study

PXE International was awarded $20,000 by the Simmons Foundation in September 1998 to conduct an epidemiological study of the manifestations and progression of PXE. Analysis of over 600 completed questionnaires gave PXE International the opportunity to study and publish papers in peer-reviewed journals:

• PXE and Pregnancy
• Mammography and PXE
• Testicular Microlithiasis and PXE
• Prominent Mental Chin Crease
• Mutation Detection in the ABCC6 Gene and Genotype-Phenotype Analysis in a Large International Case Series Affected by PXE

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Mutation Analysis

PXE International piloted a system to combine the standardization of mutation detection and the input of phenotypic information by placing three dHPLC machines in labs in Belgium and South Africa. Using state-of-the-art informatics, over 100 mutations were discovered and a basis was formed for the development of a diagnostic kit for PXE, which is now available from GeneDx.

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Diagnostic Kit

PXE International, as part of the federal Collaboration, Education and Test Translation (CETT) program, has begun to offer a genetic test for PXE through GeneDx. This is the first diagnostic test for PXE. PXE International has worked to make the test affordable, high quality, with broad access and appropriate genetic counseling. This test helps families understand if siblings of affected individuals have PXE, and may also allow therapies to be targeted to specific mutations determined by the test. 

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Cellular and Molecular Studies

PXE International is funding research in a number of labs studying cell structure and function. One such study includes cytochemical and immunocytochemical localizations, X-ray microanalysis, and confocal microscopy image analysis. This effort will be instrumental in characterizing subcellular organelle behaviors, cellular behavior, and tissue-specific phenotypes.

Another laboratory is conducting cellular protein assay experiments for functional understanding of recombinant protein using the baculovirus insect cell system. This research seeks to characterize the previously observed protein degradation, cellular response to accumulation of unfolded mutant integral membrane proteins in the endoplasmic reticulum, posttranslational modification, and purification of recombinant ABCC6/MRP6 proteins in cells using recombinant baculovirus transfer cell expression plasmids. The purpose of this work is protein purification, targeted peptide design, peptide purification, testing of customized monoclonal antibodies, protein expression characterization, enzymatic functional description, structural dynamic range, and primary functional analysis of wild type and mutant proteins.

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PXE Research Meeting

PXE International received another R13 grant for partial support for a Symposium entitled "PXE Research 2010". The meeting was held November 29 and 30, 2010 at the Bethesda North Marriott Hotel & Conference Center in suburban DC. The meeting was coordinated and co-sponsored by PXE International. This was the third international research meeting sponsored by PXE International with the help of NIH. The others took place in 1997 and 2004.

The overall goal of the meeting was to provide a forum for investigators to discuss relevant advances in transporter biology, metabolism, genetics, and epidemiology and for clinically oriented colleagues and PXE International to jointly plan for future research and translational applications. The audience represented a broad spectrum of individuals with varying expertise including practicing clinicians caring for patients with PXE, physician-scientists and basic science investigators and lay leaders, all of whom share an interest in PXE.

Read more about the 2010 PXE Research Meeting

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Clinical Study at NIH

With support from the NIH, PXE International continues to prepare a clinical trial to examine the effects of multiple treatments for the vision loss caused by PXE. This will take place at the National Institutes of Health (NIH).

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Conclusion

PXE International is in a unique and powerful position to advocate for individuals affected by PXE, and our work is vital to them and to others facing similar struggles. It is the only hope for many individuals who desperately fear blindness. PXE International is also a role model for many other groups throughout the world.

Despite the now millions of dollars we have placed into service towards PXE research via the NIH, much remains to be done. In the United States, the NIH funds basic research. While this research is critical, we need to move to the next step and look at translating research into treatments. We have a number of labs ready to work on this – it is not only up to us to garner the funds to move forward. It is essential, not only to those affected by PXE but also to other groups, to analyze the incredible gold mine of data we have gathered in our search to understand and meet the challenge of PXE. Working into the wee hours of the morning, our fatigue abates through a burning desire to prevent blindness and other difficulties for the thousands of people on our registry. And in so doing, we are creating a new model of partnership between practitioners, researchers and the individuals they serve. 

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Last updated 12/28/2010