ROCKVILLE, MD, United States

Ariadne Diagnostics, Llc

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ROCKVILLE, MD, United States
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Ayoglu B.,KTH Royal Institute of Technology | Chaouch A.,Northumbria University | Lochmuller H.,Northumbria University | Politano L.,The Second University of Naples | And 20 more authors.
EMBO Molecular Medicine | Year: 2014

Despite the recent progress in the broad-scaled analysis of proteins in body fluids, there is still a lack in protein profiling approaches for biomarkers of rare diseases. Scarcity of samples is the main obstacle hindering attempts to apply discovery driven protein profiling in rare diseases. We addressed this challenge by combining samples collected within the BIO-NMD consortium from four geographically dispersed clinical sites to identify protein markers associated with muscular dystrophy using an antibody bead array platform with 384 antibodies. Based on concordance in statistical significance and confirmatory results obtained from analysis of both serum and plasma, we identified eleven proteins associated with muscular dystrophy, among which four proteins were elevated in blood from muscular dystrophy patients: carbonic anhydrase III (CA3) and myosin light chain 3 (MYL3), both specifically expressed in slow-twitch muscle fibers and mitochondrial malate dehydrogenase 2 (MDH2) and electron transfer flavoprotein A (ETFA). Using age-matched sub-cohorts, 9 protein profiles correlating with disease progression and severity were identified, which hold promise for the development of new clinical tools for management of dystrophinopathies. © 2014 The Authors.


PubMed | Research Center for Genetic Medicine, University of Ferrara, Leiden University, The Second University of Naples and 7 more.
Type: Journal Article | Journal: EMBO molecular medicine | Year: 2014

Despite the recent progress in the broad-scaled analysis of proteins in body fluids, there is still a lack in protein profiling approaches for biomarkers of rare diseases. Scarcity of samples is the main obstacle hindering attempts to apply discovery driven protein profiling in rare diseases. We addressed this challenge by combining samples collected within the BIO-NMD consortium from four geographically dispersed clinical sites to identify protein markers associated with muscular dystrophy using an antibody bead array platform with 384 antibodies. Based on concordance in statistical significance and confirmatory results obtained from analysis of both serum and plasma, we identified eleven proteins associated with muscular dystrophy, among which four proteins were elevated in blood from muscular dystrophy patients: carbonic anhydrase III (CA3) and myosin light chain 3 (MYL3), both specifically expressed in slow-twitch muscle fibers and mitochondrial malate dehydrogenase 2 (MDH2) and electron transfer flavoprotein A (ETFA). Using age-matched sub-cohorts, 9 protein profiles correlating with disease progression and severity were identified, which hold promise for the development of new clinical tools for management of dystrophinopathies.


Grant
Agency: European Commission | Branch: FP7 | Program: CP-IP | Phase: HEALTH.2012.2.1.1-1-B | Award Amount: 16.85M | Year: 2012

Neurodegenerative (ND) and neuromuscular (NM) disease is one of the most frequent classes of rare diseases, affecting life and mobility of 500,000 patients in Europe and millions of their caregivers, family members and employers. This NEUROMICS project brings together the leading research groups in Europe, five highly innovative SMEs and relevant oversea experts using the most sophisticated Omics technologies to revolutionize diagnostics and to develop pathomechanism-based treatment for ten major ND and NM diseases. Specifically we aim to: (i) use next generation WES to increase the number of known gene loci for the most heterogeneous disease groups from about 50% to 80%, (ii) increase patient cohorts by large scale genotyping by enriched gene variant panels and NGS of so far unclassified patients and subsequent phenotyping, (iii) develop biomarkers for clinical application with a strong emphasis on presymptomatic utility and cohort stratification, (iv) combine -omics approaches to better understand pathophysiology and identify therapeutic targets, (v) identify disease modifiers in disease subgroups cohorts with extreme age of onset (vi) develop targeted therapies (to groups or personalized) using antisense oligos and histone deacetylase inhibitors, translating the consortiums expertise in clinical development from ongoing trials toward other disease groups, notably the PolyQ diseases and other NMD. To warrant that advances affect a large fraction of patients we limited the selection to a number of major categories, some of which are in a promising stage of etiological and therapeutic research while some others are in great need of further classification. The efforts will be connected through a NEUROMICS platform for impact, communication and innovation that will provide tools and procedures for ensuring trial-readiness, WP performance, sustainability, interaction with the chosen Support IRDiRC and RD-Connect project and involvement of stakeholders in the NDD/NMD field.


Kotelnikova E.,Hospital Clinic of Barcelona | Kotelnikova E.,Russian Academy of Sciences | Bernardo-Faura M.,European Bioinformatics Institute | Silberberg G.,Karolinska University Hospital | And 19 more authors.
Multiple Sclerosis Journal | Year: 2015

The pathogenesis of multiple sclerosis (MS) involves alterations to multiple pathways and processes, which represent a significant challenge for developing more-effective therapies. Systems biology approaches that study pathway dysregulation should offer benefits by integrating molecular networks and dynamic models with current biological knowledge for understanding disease heterogeneity and response to therapy. In MS, abnormalities have been identified in several cytokine-signaling pathways, as well as those of other immune receptors. Among the downstream molecules implicated are Jak/Stat, NF-Kb, ERK1/3, p38 or Jun/Fos. Together, these data suggest that MS is likely to be associated with abnormalities in apoptosis/cell death, microglia activation, blood-brain barrier functioning, immune responses, cytokine production, and/or oxidative stress, although which pathways contribute to the cascade of damage and can be modulated remains an open question. While current MS drugs target some of these pathways, others remain untouched. Here, we propose a pragmatic systems analysis approach that involves the large-scale extraction of processes and pathways relevant to MS. These data serve as a scaffold on which computational modeling can be performed to identify disease subgroups based on the contribution of different processes. Such an analysis, targeting these relevant MS-signaling pathways, offers the opportunity to accelerate the development of novel individual or combination therapies. © The Author(s), 2014.


Grant
Agency: European Commission | Branch: FP7 | Program: CP-FP | Phase: HEALTH-2009-2.4.4-1 | Award Amount: 7.54M | Year: 2009

The rapidly expanding knowledge of NMDs genetic diagnosis, pathogenesis and therapeutic possibilities has provided new targets for disease characterisation, early diagnosis, drug discovery and development as well as has raised many questions about how to translate this knowledge into clinical practice as (initial) clinical trials typically run for such a short time that clinical improvement can hardly be expected within that time frame. This militates for the discovery of surrogate endpoints for establishing the efficacy of clinical trials. The concept of biomarkers represents measurable bio-parameters able to flank the process of diagnosis, functional characterisation and therapy in NMDs. OMIC sciences (genomic, transcriptomics, proteomics) offer opportunities to identify biomarkers for finely defining and tuning the NMDs bases. This approach can make available non-invasive biomarkers, to be used for monitoring disease progression, prognosis and drugs response, therefore optimising the choice of appropriate and often personalised therapies. Validated biomarkers will increase therapy efficiency (meaning optimal dose of drug to get responders) and efficacy (responders vs non responders for example if we will identify genomic biomarkers linked to the lack of any therapeutic effect). In this case we could address a truly efficacious therapy (avoiding inefficacious treatment due to unfavourable genomic contexts). The new genomic and proteomic biomarkers discovered within BIO-NMD will be validated both in animal models and in human samples, before entering into a qualification process at the EMEA. The qualified biomarkers resulting from the BIO-NMD project will be ready for ongoing and further clinical trials for the patient benefit. This will increase the therapy efficacy and efficiency and also reduce adverse effects, with impact on patients quality of life with also economical relevance. The BIO-NMD consortium is led by the University of Ferrara, an internationally recognised university in the field of genomics of hereditary neuromuscular disorders. In addition the consortium is composed of 7 leading European academic partners bringing their expertise in all OMIC sciences as well as in bio-informatics and patient sample collection, 1 SME providing its skills in bio-informatics and 1 global company specialised in the development of patient samples screening.


PubMed | Bionure Farma SL, ProtATonce Ltd, University of Zürich, Charité - Medical University of Berlin and 6 more.
Type: Journal Article | Journal: Multiple sclerosis (Houndmills, Basingstoke, England) | Year: 2015

The pathogenesis of multiple sclerosis (MS) involves alterations to multiple pathways and processes, which represent a significant challenge for developing more-effective therapies. Systems biology approaches that study pathway dysregulation should offer benefits by integrating molecular networks and dynamic models with current biological knowledge for understanding disease heterogeneity and response to therapy. In MS, abnormalities have been identified in several cytokine-signaling pathways, as well as those of other immune receptors. Among the downstream molecules implicated are Jak/Stat, NF-Kb, ERK1/3, p38 or Jun/Fos. Together, these data suggest that MS is likely to be associated with abnormalities in apoptosis/cell death, microglia activation, blood-brain barrier functioning, immune responses, cytokine production, and/or oxidative stress, although which pathways contribute to the cascade of damage and can be modulated remains an open question. While current MS drugs target some of these pathways, others remain untouched. Here, we propose a pragmatic systems analysis approach that involves the large-scale extraction of processes and pathways relevant to MS. These data serve as a scaffold on which computational modeling can be performed to identify disease subgroups based on the contribution of different processes. Such an analysis, targeting these relevant MS-signaling pathways, offers the opportunity to accelerate the development of novel individual or combination therapies.


Slade G.D.,University of North Carolina at Chapel Hill | Smith S.B.,University of North Carolina at Chapel Hill | Zaykin D.V.,National Health Research Institute | Tchivileva I.E.,University of North Carolina at Chapel Hill | And 9 more authors.
Pain | Year: 2013

Human association studies of common genetic polymorphisms have identified many loci that are associated with risk of complex diseases, although individual loci typically have small effects. However, by envisaging genetic associations in terms of cellular pathways, rather than any specific polymorphism, combined effects of many biologically relevant alleles can be detected. The effects are likely to be most apparent in investigations of phenotypically homogenous subtypes of complex diseases. We report findings from a case-control, genetic association study of relationships between 2925 single nucleotide polymorphisms (SNPs) and 2 subtypes of a commonly occurring chronic facial pain condition, temporomandibular disorder (TMD): 1) localized TMD and 2) TMD with widespread pain. When compared to healthy controls, cases with localized TMD differed in allelic frequency of SNPs that mapped to a serotonergic receptor pathway (P = 0.0012), while cases of TMD with widespread pain differed in allelic frequency of SNPs that mapped to a T-cell receptor pathway (P = 0.0014). A risk index representing combined effects of 6 SNPs from the serotonergic pathway was associated with greater odds of localized TMD (odds ratio 2.7, P = 1.3 E-09), and the result was reproduced in a replication case-control cohort study of 639 people (odds ratio 1.6, P = 0.014). A risk index representing combined effects of 8 SNPs from the T-cell receptor pathway was associated with greater odds of TMD with widespread pain (P = 1.9 E-08), although the result was not significant in the replication cohort. These findings illustrate potential for clinical classification of chronic pain based on distinct molecular profiles and genetic background. © 2013 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

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