Patrick F. Terry

Advocacy groups as research organizations: the PXE International example.

Advocacy organizations for genetic diseases are increasingly becoming involved in biomedical research, particularly translational research, in order to meet the needs of the individuals that they serve. PXE International, an advocacy organization for the disease pseudoxanthoma elasticum, provides an example of how research can be accelerated by these groups. It has adopted methods that were pioneered by other advocacy organizations, and has integrated these along with new approaches into franchizable elements. The model has been followed for other conditions and has led to the establishment of a common infrastructure to enable advocacy groups to initiate, conduct and accelerate research.

Mutation Detection in the ABCC6 Gene and Genotype-Phenotype Analysis in a Large International Case Series Affected by Pseudoxanthoma Elasticum

Background: Pseudoxanthoma elasticum (PXE), an autosomal recessive disorder with considerable phenotypic variability, mainly affects the eyes, skin and cardiovascular system, characterised by dystrophic mineralization of connective tissues. It is caused by mutations in the ABCC6 (ATP binding cassette family C member 6) gene, which encodes MRP6 (multidrug resistance-associated protein 6). Objective: To investigate the mutation spectrum of ABCC6 and possible genotype–phenotype correlations. Methods: Mutation data were collected on an international case series of 270 patients with PXE (239 probands, 31 affected family members). A denaturing high-performance liquid chromatography-based assay was developed to screen for mutations in all 31 exons, eliminating pseudogene coamplification. In 134 patients with a known phenotype and both mutations identified, genotype–phenotype correlations were assessed. Results: In total, 316 mutant alleles in ABCC6, including 39 novel mutations, were identified in 239 probands. Mutations were found to cluster in exons 24 and 28, corresponding to the second nucleotide-binding fold and the last intracellular domain of the protein. Together with the recurrent R1141X and del23–29 mutations, these mutations accounted for 71.5% of the total individual mutations identified. Genotype–phenotype analysis failed to reveal a significant correlation between the types of mutations identified or their predicted effect on the expression of the protein and the age of onset and severity of the disease. Conclusions: This study emphasises the principal role of ABCC6 mutations in the pathogenesis of PXE, but the reasons for phenotypic variability remain to be explored.

Pseudoxanthoma elasticum: progress in diagnostics and research towards treatment : Summary of the 2010 PXE International Research Meeting.

Pseudoxanthoma elasticum (PXE), a prototypic heritable disorder with ectopic mineralization, manifests with characteristic skin findings, ocular involvement, and cardiovascular problems. The classic forms of PXE are due to loss‐of‐function mutations in the ABCC6 gene, which encodes ABCC6, a putative transmembrane efflux transporter expressed primarily in the liver. While considerable progress has recently been made in understanding the molecular genetics and pathomechanisms of PXE, no effective or specific treatment is currently available for this disorder. PXE International, the premiere patient advocacy organization, organized a workshop in November 2010 to assess the current state of diagnostics and research to develop an agenda towards treatment of PXE. This overview summarizes the progress in PXE research, with emphasis on molecular therapies for this, currently intractable, disorder.

Power to the People: Participant Ownership of Clinical Trial Data

The time has come to crowd-source data for diagnostic and therapeutics development. Participation in clinical trials is dismally low. In this age of electronic sharing of information of all sorts, trial participants can easily share clinical trial data. The benefits of participant ownership and sharing of trial data appear to outweigh the risks. Thus, the time has come to crowd-source data for diagnostic and therapy development.

Pseudoxanthoma Elasticum: Progress in Research Toward Treatment: Summary of the 2012 PXE International Research Meeting

Pseudoxanthoma elasticum (PXE) is amultisystem disorder manifesting pri-marily with clinical findings in the skin,the eyes, and the cardiovascular system,with considerable morbidity and occa-sional mortality (Neldner, 1988; Uittoet al., 2010). The precise prevalence ofPXE is currently unknown, but it isclearly a rare disease. Nevertheless, theprevalence has been suggested to beB1:50,000, which would imply thatthere are B7,000 affected individualsin the United States and as many as150,000 in the world assuming the sameglobal prevalence (Uitto, 2012). PXE isinherited in an autosomal recessivemanner caused by mutations in theABCC6 gene that encodes ATP-BindingCassette, family C, number 6 protein,ABCC6. This transmembrane effluxtransporter is expressed primarily in theliver, and to some extent in the kidneysand the intestine, but at very low levels,if at all, in tissues directly affected byPXE. Previous observations on patientswith PXE, as well as studies utilizing aknockout mouse model, Abcc6

An End to the Myth: There Is No Drug Development Pipeline

A new map is presented for creating an open, collaborative, and coordinated system for drug development. A new map is presented for creating an open, collaborative, and coordinated system for drug development.

Genetic Alliance Registry and BioBank: a novel disease advocacy-driven research solution

The Genetic Alliance Registry and BioBank was founded in 2003 on the principal that a shared infrastructure would facilitate easy flow of resources and accelerate disease-specific research. Based on the Pseudoxanthoma Elasticum International Registry and BioBank, six disease advocacy organizations came together to identify the best solutions for advocacy organizations to promote and collect biological samples with associated clinical information from their members. This required a flexible system that could accommodate an extensive amount of data and samples, support new avenues of research, yet be adaptable to meet the needs of a variety of organizations, and straightforward to implement and use. After extensive landscape analyses, a cross-disease, infinitely expandable registry and biorepository was established. This article reports on this effort and shares the lessons learned.

A Consumer Perspective on Forensic DNA Banking

This article describes a model of DNA banking that incorporates appropriate consumer influence on the design and use of DNA data banks. This model values input of consumer stakeholders in key decisions, including contracts between donors, researchers and the bank.

A consumer perspective on informed consent and third-party issues.

&NA; Our two children were diagnosed with a rare genetic disorder, which led us to establish a research foundation. This led to in‐depth consideration of issues surrounding informed consent from a consumer perspective. Third‐party issues arose as central to the formulation of ethical policy in the establishment of a blood and tissue bank and an epidemiologic study. We suggest that a number of myths–privacy is possible, samples can be stripped of identifiers, humans are subjects, voluntary informed consent is attainable, genetics is about the individual only, genetic information is different than other medical information, research is altruistic, the public will learn truths about genetic research via media, and research is culturally competent–make it difficult to resolve the issues intrinsic to informed consent. A number of important elements could make policy decisions less complicated. These include conducting culturally competent research; conveying noncoercive hope, not hype; contacting the voluntary informant only; asking the informant to extend contact to other family members; requiring a comprehensive informed consent process for all contacted; and engaging in state‐of‐the‐art data protections. There is a need for a “Genomic Hippocratic Oath,” creating an ethical basis for research similar to the one vowed by health care professionals. Establishing ethical policies as a result of the collaboration of policy makers, researchers, and consumers will allow research to progress ethically at a rapid rate. If regulations are oppressive, they will thwart research; if they are too lenient, participants will not receive protections needed to participate safely.