2006 State of the Foundation Report

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State of the Foundation Report

January 1, 2006

 

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

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).

Fig1
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

 

Groundwork

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.

All activities are 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-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 – see below.

 

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.)

 

Epidemiological Study

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 (Attach), Mammography and PXE (Attach), Testicular Microlithiasis and PXE (Attach).  We are in the process of analyzing the pediatric data 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.

 

Mutation Analysis

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 were 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, we 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.

 

Diagnostic Kit

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.  Our 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 producing a comprehensive summary of the PXE 2004 Research Meeting (available upon request). 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.  This 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. 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 this 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 development of a formal research consortium was a major result of this meeting.  This will allow us to proceed with a clinical study.  The major issues that resulted are:

Genotype/Phenotype

Geno/pheno correlations

Variability in penetrance, expressivity and progression

From mutations to phenotypes

Identical genotypes –

Genotype people without mutations in the coding region

 

Genetics

Is there another locus?  SNPs

Modifier genes- find that locus

Gene chips?

Another locus, noncoding region

Is the deletion a problem?

 

Gene & Protein Function

Function of MRP6

Look at MRP expression over lifespan

Post translational modification

Normal function

Consequences of mutations – allelic therapeutic approach

Validated assay – small molecule screening- both molecules that block and those that perform, whole family screening

Synonymous alterations – codon usage – alternative splicing

Antibodies expression – in the ones you cannot find mutations

Inside out vesicles – purify and put them in

Make chimeric protein – Jouni didn’t find anything

GFP reporter

Inhibitors – hepatosycle +/- inhibitors

Basic Bruch’s membrane – research angiogenesis, roll of ABCC6 in eye – choroidal fibroblasts?

 

Environmental factors

 

Diagnostic

Understand diagnostic criteria – what we will we accept as biomarker

Place for DNA diagnostics – to determine potential treatment protocols

Need to narrow the clinical diagnosis

Definitive statement – recessive inheritance

Diagnostic criteria

Females to males – genotype sibs and families

 

Models

Characterize mouse model for mechanisms of mineralization

Liver expression – mouse liver transplant

Regulation of MRP6 – at protein level – like MRP2 – targeting and cycling – Put PDZ on MRP6 Would it appear in bile of mouse – do mass spec – at transcriptional level

Evolutionary and embryonic models – c. elegans

Find models – smaller and larger

Zebra fish – when does gene turn on why – is it in the eye/

 

Pathobiology

Assay for pump function

What about overexpression – cytotoxic drugs and the mouse redox system

Can we distinguish between PXE and normal cells?

What compounds might make the PXE cell look like a normal cell?

Pathomechanisms

Pathobiology

 

Clinical Study

NIH clinical study – develop protocol

 

Treatments

Treatments, model systems?

Issues of antioxidants reversing damage?

Treatments of cells with small molecules

Use RNAi

 

Research Structure

Consortium – clinical and molecular

 

Clinical Study at NIH

 

With support from the NIH, PXE International is about to launch a 3-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, we will be looking at a variety of possible treatments and interventions, with the goal of establishing a clinical trial in the three-year project.

 

Conclusion

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 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, 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 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.

 

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