PXE International is a non-profit organization in the United States. PXE International initiates, funds and conducts research; provides support for individuals and families affected by pseudoxanthoma elasticum; and provides resources for healthcare professionals.
The organization is supported by grants from the U.S. government, the Simmons Foundation, Transgenomic, Inc., and private donations.
Patrick F. Terry was a designer and engineer and Sharon F. Terry was a former college chaplain when they learned in 1994 that their children had PXE. Although they had no formal scientific background, they read medical literature, met with scientists and crafted a comprehensive research plan (Figure 1).
The principles of the design for the foundation are:
- Fast track all phases of research simultaneously in order to avoid bottlenecks
- Position the foundation as a conduit 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
The Terrys established PXE International as a 501(c)(3) with the help of Lionel Bercovitch, MD, of Brown University. Dr. Bercovitch is trained in both dermatology and ophthalmology and has volunteered extensively for the foundation. A dedicated board and staff provide expertise and assistance.
During the first few years, PXE International:
- Assessed the state of PXE research. This included 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 (Figure 2) to form the cohort needed for robust studies.
- Founded the PXE International Blood and Tissue Bank, whose samples now number in the thousands. This lay-managed and -owned bank was the first of its kind and is the model on which the Genetic Alliance BioBank is founded.
The PXE International Blood and Tissue Bank accelerated the discovery of the PXE gene. As a result of their material involvement in the discovery, PXE International is a co-owner of the patent on the PXE gene. The patent issued in August 2004. It has been licensed to GeneDx for the diagnostic test.
Two back-to-back papers appeared in Nature Genetics describing the PXE gene.
Seeding various projects paid off for PXE International; they first began to be awarded grant money in September 1998. The Simmons Foundation awarded PXE International a grant of $20,000 for an epidemiological study of the manifestations and progression of PXE in a large number of individuals. Over 600 questionnaires were completed. The Center for Disease Control in Atlanta, GA, donated time to help analyze the data.
Although there are a large number of case studies on PXE, it is necessary to analyze data on a large group of individuals in order to understand the wide spectrum of the condition. In fact, case reports tend to focus on individuals with the most severe signs and symptoms, leading clinicians and patients to think the disease is worse than it is. Analysis of the data is almost complete and plans for correlating the data to genetic information about individuals are under way.
In the process of analyzing the data from over 600 surveys, PXE International was able to study and publish papers in peer-reviewed journals. These include a study on PXE and pregnancy , mammography and PXE , and testicular microlithiasis and PXE . At this time, pediatric data is being analyzed to describe the natural history of PXE in children.
Other genetics groups recognize PXE International for its profoundly innovative approach to research of rare diseases. PXE International is lauded internationally for creating a new paradigm for lay advocacy groups initiating and conducting research. Articles have appeared in major newspapers and magazines describing the novelty and progression of the model.
PXE International piloted a system to combine the standardization of mutation detection and the input of phenotypic information. PXE International placed three dHPLC machines in labs in Philadelphia, Ghent (Belgium) and Johannesburg (South Africa). State-of-the-art informatics was used to analyze the data. To date we have discovered over 270 mutations as a result of this work. In addition, this work formed the basis of the development of a diagnostic test for pseudoxanthoma elasticum.
Using advanced statistical software, it was determined that correlations between mutations with clinical phenotype do not exist. Several sub-studies evolved from the mutation analysis, including one in multiple generation families, and one a rare phenotype of PXE with eye but no skin manifestations.
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.
PXE research meeting
PXE International is co-sponsoring a PXE research meeting in September 2009. Many scientists, clinicians, and patients have been invited to attend. In addition to exchanging information, people at the meeting can coordinate future grant proposals.
Clinical study at National Institutes of Health
With support from the U.S.'s National Institutes of Health, PXE International is about to launch a three-year clinical investigation into the manifestations of PXE. This study will focus on characterizing the clinical manifestations of PXE. After the initial characterization, a variety of possible treatments and interventions will be examined with the goal of establishing a clinical trial in the three-year project.
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