SSIEM 2016 Day 2 summaries of Dr Simmons, Dr Lee, Dr Emma and Dr Auray-Blais

 In Congresses, Fabry Disease, Hunter Syndrome

We had another exciting day at SSIEM in Rome where we attended a number of lectures and heard about innovative new technologies and biomarkers in the rare disease space. We have highlighted a number of those lectures below, including those of Dr Simmons, Dr Lee, Dr Emma and Dr Auray-Blais. Read more about their talks and visit the Rare 2 Aware blog again for more information from leaders in the rare disease space. F Emma: New technologies to find new active molecules Dr Francesco Emma shared his insights into setting up a high-throughput screening (HTS) method for new active compounds from his experience of a HTS in cystinosis, in which he identified disulfiram as a potential new treatment. He noted that what you need is:

  • appropriate cell line e.g. he used epithelial tubular kidney cells
  • good assay with good controls e.g. he assayed both cystine content and apoptosis, using cysteamine (current treatment) and cycloheximide as controls respectively
  • suitable small molecule library e.g. he used the Prestwick chemical library

Dr Emma suggested that this chemical library is a good starting place for HTS in rare diseases because it contains 90% of drugs already licensed for human use and has pharmacological diversity. Dr Emma’s next steps in the HTS were to identify compounds that were effective in both assays, then rule out compounds with poor safety profiles and those that didn’t act within the therapeutic concentration range possible. B H Lee: Identification of a new biomarker in Fabry disease by plasma proteomic analysis Dr Lee presented initial evidence to suggest that the iC3B protein could be a potential biomarker for monitoring the response to treatment in Fabry disease. This protein is part of the complement system. Dr Lee shared results of a proteomic analysis (2D SDS-PAGE and MS/MS analysis) of plasma samples from 8 patients collected before and after ERT therapy, supplemented by western blot analysis. Of the 15 proteins that were differentially regulated, iC3B appeared to be the best candidate to reflect changes induced by therapy because its expression gradually decreased through time on treatment, mirroring GB3 changes, and even appeared to show a transient elevation during the period of time when an enzyme shortage led to a disturbance of the treatment regimen. Tests also suggested that prior to ERT, expression levels of iC3B were higher than age/gender-matched controls. Dr Lee did not think that the iC3B changes were a result of an immune response to the therapy because the C4B protein that is known to be involved in the antibody-mediated immune response did not show the same gradual decrease over time. However, Dr Lee noted that a larger study is needed to rule this possibility out and to validate iC3B as a biomarker. L T Simmons: Multi-omics tools for the diagnosis and treatment of rare neurological disease Dr Simmons presented results from a cohort study of early onset epileptic encephalopathy (EE) patients using a combined whole exome sequencing and untargeted metabolomic analysis method to identify previously undiagnosed cases of EE. EE can be caused by a range of rare genetic disorders. Therefore when patients present with EE, the cause of their condition is often unknown. Dr Simmons demonstrated that whole exome sequencing can be complemented by untargeted metabolomic analysis to reveal both novel mutations and evidence of the pathogenicity of mutations. He also highlighted that the metabolomic data can be mined further to identify metabolic fingerprints for disorders and to elucidate new testing and screening methods. C Auray Blais: A reliable multiplex mass spectrometry analysis of glycosaminoglycans for mucopolysaccharidoses Dr Auray-Blais shared with us her concerns that clinicians rely on the dimethylene blue (DMB) spectrophotometric analysis of total urinary GAGs to diagnose and monitor MPS patients: interfering substances can lead to false positives and aggregation with other substances can cause false negatives. Dr Auray-Blais presented her work on developing an alternative multiplex method that analyses a series of biomarkers (dermatan sulfate, heparan sulfate, keratan sulfate and chondroitin sulfate) to help diagnose MPS I, II, III, IV and VI. The clear benefits of this new method were demonstrated in a test set of 23 samples, in which 30% of positive results picked up by this method would have been missed using DMB analysis. The method uses ultra performance liquid chromatography and mass spectrometry of methanol-extracted urine samples with deuterated internal standards added. The method offers high-specificity and the inter-day and intra-day precision was acceptable, indicating that the method is robust and reliable. Dr Auray-Blais hopes that in the near future this method could be adapted for use on urine samples collected on filter paper and send by mail and that newborn screening could also be carried out on urine samples. INTSP/C-ANPROM/RDBU/16/0034 September 2016 The post SSIEM 2016 Day 2 summaries of Dr Simmons, Dr Lee, Dr Emma and Dr Auray-Blais appeared first on Rare2Aware.

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