State of the Foundation Report
September 30, 2007
End of Fiscal Year 2007
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.
Pat was a designer and engineer 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 crafted a comprehensive research plan (Figure 1).
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
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 is selflessly dedicated to long hours of volunteer work 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.
PXE International staffing grew in a meaningful way this year. Delia Clayton was hired as the second full-time employee, as assistant director, to join Sharon Terry, who serves as Executive Director. In addition, Emilie Lamb was hired as the second part-time research assistant, to replace Sophia Vourthis, who graduated and returned to Washington State. Christine Vocke was promoted to Director of Education and Information. Terry Mac Dermaid continues as webmaster, and Mary Peckiconis as bookkeeper. Donna Foster continues to oversee the books. Mary LeBlanc serves in a volunteer capacity as listserv manager.
Discovery of the Gene Associated with PXE
The PXE International Blood and Tissue Bank accelerated the discovery of the PXE gene, and the research was enhanced by the participation of Patrick and Sharon Terry. 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 Transgenomic for development of a diagnostic test. Refer to the section titled Diagnostic Kit.
Sharon Terry is a co-author on two back-to-back papers in Nature Genetics describing the PXE gene. This is unique for two reasons. When papers are published back-to-back, it is rare that one author collaborates with both groups. PXE International works extensively with both of the labs that published in that issue and helped to coordinate the simultaneous publication. It is also exceedingly rare for a non-Ph.D./M.D. to publish a paper in a journal of such high impact. (Ms. Terry has an M.A. in Religious Studies.)
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 forms 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.
PXE International, as part of the federal Collaboration, Education and Test Translation program, has begun to offer a genetic test for PXE. This is first diagnostic test for PXE. We have worked, with GeneDx, 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.
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 applying for another R13 grant for partial support for a Symposium entitled "PXE Research 2008". The meeting will be held September 2008 at the North Bethesda Marriott in suburban DC. The meeting will be coordinated and co-sponsored by PXE International.
The overall goal of the meeting will be 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 will represent 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.
Clinical Study at NIH
With support from the NIH, 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 – something that is not often done well in rare diseases, which usually are characterized by case reports of the extremes of the phenotype. 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.
PXE International in the Genetics Community
Sharon and/or Patrick Terry serve on these committees, which give the foundation a central position in the genetics community:
- President & CEO, Genetic Alliance
- Founding President, Genetic Alliance BioBank
- Member, Google Health Advisory Board
- Founder, Personalized Medicine Coalition Board of Directors
- Founding member, 21st Century Medicine Coalition
- Founding President, International Genetic Alliance (IGA)
- Founder, Genomic Health, Inc.
- Member, Institute of Medicine Translational Research Roundtable
- President, Coalition for Genetic Fairness
- Liaison, National Advisory Council for Human Genome Research
- Member, Colorectal Cancer Coalition Advisory Board
- Member, Cellular, Tissue, and Gene Therapies Advisory Committee, FDA (formerly Center for Biologics Evaluation and Research Advisory Committee, FDA)
- Member, Center on Information and Study on Clinical Research Participation (CISCRP) Board of Directors
- Member, DNA Direct Board of Directors
- Office of Rare Diseases, NIH and CDC, Rare Disease Testing Working Group
- Member, Genetics Services Research Advisory Board
- Member, Biotechnology Institute Board of Directors
- Member, Scientific Council, PXE France
- Member, Professional Advisory Board, Autosomal Recessive Polycystic Kidney Disease Alliance
- Chair, American Society of Human Genetics Social Issues Committee
- Member, Professional Advisory Board, Aneurysm Outreach Inc.
- Member, Advisory Committee on Informed Consent, Centers for Disease Control, Atlanta, Georgia
- Co-President, Coalition of Heritable Disorders of Connective Tissue
- Founder, Co-chair, Coalition of Advocates for Research on the Eye (CARE)
Except for projects supported by grants from the Simmons Foundation, NIH and Transgenomic, all PXE International research is funded through private donations. The seeds planted by these small donations have grown into grants from foundations, companies and the government.
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 advocacy groups throughout the world.
Despite the now millions of dollars we have placed into service on PXE research via the NIH, much remains to be done. In the United States, the NIH funds basic research. While this research is critical, PXE International needs to move to the next step and look at translating research into treatments. There are a number of labs ready to work on this – it is 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 gathered in the search to understand and meet the challenge of PXE. Working into the wee hours of the morning, fatigue abates through a burning desire to prevent blindness and other difficulties for the thousands of people on the PXE International registry, and in so doing, to create a new model of partnership between practitioners and researchers and the individuals they serve.
 Bercovitch L, Leroux T, Terry S, Weinstock MA.Pregnancy and obstetrical outcomes in pseudoxanthoma elasticum. British Journal of Dermatology. 2004;151:1011-1018.
 Bercovitch L, Schepps B, Koelliker S, Magro C, Terry S, Lebwohl M. Mammographic findings in pseudoxanthoma elasticum. Journal of the American Academy of Dermatology.2003;48:359-66.
 Bercovitch RS, Januario JJ, Terry SF, Boekeheide K, Podis AD, Dupuy DE, Bercovitch LG. Testicular microlithiasis in pseudoxanthoma elasticum. Radiology. In press, 2005.