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.

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.

Development of a rapid, reliable genetic test for pseudoxanthoma elasticum.

Mutations in the human ABCC6 gene cause pseudoxanthoma elasticum (PXE), a hereditary disorder that impacts the skin, eyes, and cardiovascular system. Currently, the diagnosis of PXE is based on physical findings and histological examination of a biopsy of affected skin. We have combined two simple, polymerase chain reaction (PCR)-based methods to develop a rapid, reliable genetic assay for the majority of known PXE mutations. After PCR amplification and heteroduplex formation, mutations in exon 24 and exon 28 of the ABCC6 gene were detected with Surveyor nuclease, which cleaves double-stranded DNA at any mismatch site. Mutations originating from deletion of a segment of the ABCC6 gene between exon 23 and exon 29 (ex23_ex29del) were detected by long-range PCR. Size analysis of digestion fragments and long-range PCR products was performed by agarose gel electrophoresis. The methods accurately identified mutations or the absence thereof in 16 affected individuals as confirmed by DNA sequencing. Fifteen patients had one or two point mutations, and two of these individuals carried the ex23_ex29del in their second allele. This mutation detection and mapping strategy provides a simple and reliable genetic assay to assist in diagnosis of PXE, differential diagnosis of PXE-like conditions, and study of PXE genetics.

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.

Power to the people: participant ownership of clinical trial data.

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.

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.

Market access challenges in the EU for high medical value diagnostic tests.

The clinical utility and medico-economic value of several personalized diagnostic tests has been well described in the literature. Development of such tests, including generation of the necessary supportive clinical validation data, is a complex and expensive endeavor. In general, sponsors of such tests lack sufficient clarity on appropriate reimbursement and regulatory pathways to provide the clear development framework necessary to incentivize the required level of investment. In the USA, an imperfect reimbursement paradigm has evolved to accommodate a small number of 'value-priced' laboratory-developed tests, although major structural barriers remain to broader implementation. In Europe, by contrast, there is virtually no precedent for value-based public sector pricing, and even such procedurally based pricing as currently exists is administered by a complex network of largely decentralized bodies. As a consequence, patient access is limited and health-economic savings are not realized. This article explores some of the European market entry barriers, with a focus on reimbursement challenges, and highlights some collaborative proposals to address such.

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.