State of the Foundation Report
June 30, 2002
Patrick and Sharon Terry founded PXE International in 1995 to create the interest and support necessary to accelerate research into the cause and 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 met with scientists who had authored scientific papers about PXE and crafted a 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 with the help of Lionel Bercovitch, MD. 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 now a model for other disease groups.
- All activities were funded through private donations.
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 result of their material involvement in the discovery, PXE International is a co-applicant for the patent on the PXE gene.
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; the 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.
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 (See Attachment A ñ Kolata, A Familyís Goal is Met and a Gene is Found, New York Times, May 28, 2000; Attachment B ñ Solovich, The Citizen Scientists, Wired Magazine, September 9, 2001 [http://www.wired.com/wired/archive/9.09/disease.html] and Attachment C ñ Allen, Who Owns My Disease?, Mother Jones Magazine, November/December 2001 [http://www.motherjones.com/magazine/ND01/gene.html]).
PXE International is piloting a system to combine the standardization of mutation detection and the input of phenotypic information. The search for mutations in the PXE gene continues, using the PXE International Blood and Tissue Bank. PXE International placed four dHPLC machines in labs in Philadelphia, Honolulu, Ghent (Belgium) and Johannesburg (South Africa). State-of-the-art informatics will be used to analyze the data.
Using advanced statistical software, we will correlate mutations with phenotype, and several advances will be possible. It will be possible to predict the manifestations toward which an individual with PXE might be predisposed. This would allow modifications of diet and lifestyle that might mitigate some of the effects of PXE. It will be possible to determine if an individual is a carrier of the gene and so may be predisposed to other conditions or symptoms, such as cardiovascular disease (Attachment D ñ UH Discovery May Cut Heart Disease, The Honolulu Star, June 2, 2002 [http://www.pxe.org/news/honolulu_060200.html]).
Most important, this correlation may lead to ideas about treatments and cure. If researchers determine that a specific mutation causes blindness, then knowing how to reverse the effects of that mutation will be crucial in slowing and stopping the progression of PXE.
PXE International is funding the creation of a knockout mouse and will examine the effects of this alteration on the mouse. Although PXE in the mouse might manifest itself quite differently from PXE in humans, the researcher we have funded at Jackson Laboratory is exceptionally skilled in discovering the parallels between mouse and human phenotypes. This research will aid in the discovery of the effects of PXE on various body systems.
Since preliminary data indicates that clinical phenotypes do not correlate with genotype, this project expands the concept of phenotype to include cellular and molecular characteristics.
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 will conduct the 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 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, Genetic Alliance
- President, Coalition of Heritable Disorders of Connective Tissue
- Co-Chair, Coalition of Patient Advocates for Skin Disease Research
- Founder, Co-Chair, Coalition of Advocates for Research on the Eye (CARE)
- Member, Ad Hoc Committee for Consumer Issues, American Society of Human Genetics
- Member, Information and Education Committee, American Society of Human Genetics
- Consumer Representative, Womenís Dermatology Committee, American Academy of Dermatology
- Representative, Research Council, American Academy of Dermatology
- Member, Ethical, Legal and Social Issues Research Advisors, National Institutes of Health
- Member, HapMap Advisory Group, National Human Genome Research Institute, National Institutes of Health
- Member, Advisory Committee on Informed Consent, Centers for Disease Control, Atlanta, GA
- Member, Ad Hoc Committee of Experts on IRBs and Informed Consent, HHS Secretary's Advisory Council on Genetic Testing
- Member, Professional Advisory Board, Aneurysm Outreach Inc.
- Member, Professional Advisory Board, Autosomal Recessive Polycystic Kidney Disease Alliance
- Member, Board of Directors, Biotechnology Institute
Except for projects supported by grants from the Simmons Foundation and Transgenomic, all PXE International research was funded through private donations. The seeds planted by these small donations have grown into grants from foundations, companies and the government. National Institutes of Health Funding for PXE totaled four million dollars as a direct result of preliminary data gathered with the support of PXE International.
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 (Attachment E ñ Keynote from the PXE Gala, Attachment F ñ Researching the Biology of PXE: Partnering in the Process, Terry and Boyd, 2001).
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, 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 ñ it is 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, to create a new model of partnership between practitioners and researchers and the individuals they serve.