State of the Foundation Report
January 1, 2005
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.
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. Over 100 mutations were discovered as a result of this work. In addition, it forms the basis of the development of a diagnostic kit 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 is bringing a diagnostic test to the FDA for approval. This will be the first diagnostic test for a rare disease to be presented to the FDA. The intention is to make the test affordable, of the highest quality, with broad access and appropriate genetic counseling. This test will not only help families understand if siblings of affected individuals have PXE, but may also allow therapies to be targeted to specific mutations determine 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
A major accomplishment this year was the PXE 2004 Research Meeting. PXE International was awarded an R13 grant for partial support for a Symposium entitled "PXE Research 2004". The meeting was held October 13 and 14, 2004 at the Pooks Hill Marriott, Bethesda, MD, a handicapped accessible hotel. The meeting was coordinated and co-sponsored by PXE International.
The Symposium capitalized on significant progress made in basic understanding of the genetics of PXE and the structural components affected by PXE since the last research meeting in 1997. Though these advances were significant, they highlighted a lack of linkage between the basic genetic and molecular advances and the pathogenesis of this disease. This meeting reviewed progress in genetics, cellular and molecular biology, catalyzed the current research through knowledge and tools of related research, provided the foundation with a comprehensive research plan and determined best practices for clinical care of individuals affected by PXE.
The overall goal of the Symposium 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.
The specific aim of the Symposium was to provide a forum for a cross-fertilization of ideas between the basic and clinical sciences that was not achievable in more general meetings, and that is essential to translational research. The presence of clinical investigators from the disciplines of dermatology, ophthalmology, gastroenterology and cardiology allowed broad-based discussion of PXE with its many systemic effects, to inform the basic science to focus it, and conversely to set best practice standards for data collection and clinical care. Special attention was paid to the involvement of women, young investigators and trainees in this meeting, and involving both scientists and clinicians from underrepresented communities.
The development of a formal research consortium was a major result of this meeting. This will allow us to proceed with a clinical study.
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
- Founder, Personalized Medicine Coalition Board of Directors
- Founding President, International Genetic Alliance (IGA)
- Founder, Genomic Health, Inc.
- 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
- President, Genetic Alliance Biobank Board of Directors
- Member, National Institute of Arthritis Musculoskeletal and Skin Diseases Council
- Member, Biotechnology Institute Board of Directors
- Member, American Society of Matrix Biology Council
- Member, Advisory Board, Genetics and Public Policy Center, Johns Hopkins University
- Member, Scientific Council, PXE France
- Member, Professional Advisory Board, Autosomal Recessive Polycystic Kidney Disease Alliance
- Appointed Member, The American Society of Human Genetics Information and Education Commitee
- Member, Professional Advisory Board, Aneurysm Outreach Inc.
- Ad Hoc Committee of Experts on IRBs and Informed Consent, HHS Secretary's Advisory Council on Genetic Testing
- Member, Advisory Committee on Informed Consent, Centers for Disease Control, Atlanta, Georgia
- Appointed Member, Ethical, Legal and Social Issues Research Advisors, NIH
- President, Coalition of Heritable Disorders of Connective Tissue
- Representative to the Research Council, American Academy of Dermatology
- Consumer representative, Women’s Dermatology Committee, American Academy of Dermatology
- Member, Ad-hoc Committee for Consumer Issues, The American Society of Human Genetics
- 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.