Final Report Summary - UEPHA-MS (United Europeans for the Development of Pharmacogenomics in Multiple Sclerosis)
UEPHA*MS Website: http://www.reem.es/uepha-ms/
Multiple sclerosis (MS) is a chronic inflammatory disabling disorder of the central nervous system for which no definitive cure is available. The disease is typified by a high degree of heterogeneity in the clinical presentation and disease course, brain lesion pathology, and response to therapy. The modern scenario of MS treatment with a rapidly increasing compendium of therapeutic strategies on offer to patients, taken together with the potential risk for treatment failure and adverse drug reactions, sets pharmacogenomicsat the forefront of MS research. The FP7 Initial Training Network “United Europeans for development of PHArmacogenomics in Multiple Sclerosis” (UEPHA*MS, 2008-2012) has focused on the omics-driven identification and ensuing validation of pharmacogenomic determinants of disease-modifying treatments in MS, mainly relating to interferon-beta (IFN-beta), glatiramer acetate (GA) and natalizumab. Both the former drugs are the most commonly used first-line treatments for MS that, however, are only partially effective (only 30-50% of patients respond beneficially to these therapies). This research program has led to several scientific breakthroughs reported in numerous scientific articles published / submitted by the network member groups. Of special relevance are: (i) the identification of Toll-like receptor 4 (TLR4) and Type I IFN signalling pathways as determinants of response to IFN-beta; (ii) of novel, highly sensitive IFN-beta bioavailability markers, such as USP18 and HERC; (iii) the finding that Natural Killer (NK) cell maturation is a requisite for clinical response to mitoxantrone, a drug approved for treatment of progressive MS; (iv) that various disease-modifying treatments enhance the modulatory role of CD56bright NK cells in MS; (iv) the identification of Natalizumab-driven changes in the cerebrospinal fluid proteome in MS, and of (v) multi-gene patterns associated with GA and IFN-eta efficacies. Moreover, an extensive validation study is still going on, in which 384 single nucleotide polymorphisms are being genotyped that were selected on the basis of 2 recent pharmacogenomics/IFN-eta genome-wide association studies and of our current understanding of biological pathways involved in IFN-eta response. This is done in 1050 MS patients. Thus, UEPHA-MS has generated a significant amount of new foreground data on drug response biomarkers and several new patent applications are in process. However, for the successful implementation of patient monitoring in clinical practice through biomarkers, availability of pharmacogenomic biomarkers only is unlikely to be sufficient. For instance, specific omics signatures may distinguish a favourable therapeutic response in aggressive MS from a more benign course of disease in non-responders, - a discernment that is difficult to make by clinical measures only. Since MS is a heterogeneous disease, predictive and diagnostic biomarkers are essential to categorize more robustly and more objectively the discrete types and presentations of the disorder. Ultimately, this will generate tangible benefits for MS patients via the precise targeting of novel / existing drugs to biomarker-defined subgroups of patients. In order to achieve progress in this latter categories of biomarkers, UEPHA*MS scientists identified a gene expression pattern that provides an accurate prediction of MS severity in the short-term and that substantiates a role for T and B lymphocyte activation pathways in MS severity. In addition, chitinase 3 like 1 (CHI3L1) was identified as a powerful prognostic biomarker for conversion of patients with clinically isolated syndromes (CIS) to MS. Finally, a novel haplotype of two non-synonymous SNPs at the MS risk locus CD6 was identified that is strongly associated with susceptibility to the disease.
As a training network, UEPHA*MS has been instrumental in training 11 young investigators in cutting-edge technologies for biomarker reseach including omics, cell-based, molecular biology, bioinformatics and systems biology skills. This was accomplished through in–lab training but also via a series of network-wide training courses. UEPHA*MS provided the following network-wide training courses: “Statistical Aspects of Pharmacogenomics Research” (Bilbao, June 2009), and 3 Summer Schools “School 1: Technologies for Biomarker Discovery” (Toulouse, September 2009), “School 2: Systems Biology” (Barcelona, October 2010) and "School 3: The Clinical Validation Process" (Berlin, September 2011), as well as a theoretical / hands-on “Proteomics Workshop” (Rotterdam, March 2010), biotech company visits to Progenika Biopharma and the bio-incubator for biotech start-ups Biokabi followed by an "Outreach" meeting with multiple sclerosis (MS) patients (Bilbao, April 2011). The network activity culminated in a heavily attended conference "Multiple Sclerosis and the Omics Spring" (Bilbao, 15-17 April 2012). Dedicated transferable skills training in in communication skills & ethics, project- and self-management, and entrepreneurship and IPR, were imparted as part of the Summer Schools.
In conclusion, UEPHA*MS has generated significant new knowledge on biomarkers for MS drugs, but also for diagnosis and prognosis. This information will be useful to make patient & drug management and monitoring in MS much more precise and effective.
Multiple sclerosis (MS) is a chronic inflammatory disabling disorder of the central nervous system for which no definitive cure is available. The disease is typified by a high degree of heterogeneity in the clinical presentation and disease course, brain lesion pathology, and response to therapy. The modern scenario of MS treatment with a rapidly increasing compendium of therapeutic strategies on offer to patients, taken together with the potential risk for treatment failure and adverse drug reactions, sets pharmacogenomicsat the forefront of MS research. The FP7 Initial Training Network “United Europeans for development of PHArmacogenomics in Multiple Sclerosis” (UEPHA*MS, 2008-2012) has focused on the omics-driven identification and ensuing validation of pharmacogenomic determinants of disease-modifying treatments in MS, mainly relating to interferon-beta (IFN-beta), glatiramer acetate (GA) and natalizumab. Both the former drugs are the most commonly used first-line treatments for MS that, however, are only partially effective (only 30-50% of patients respond beneficially to these therapies). This research program has led to several scientific breakthroughs reported in numerous scientific articles published / submitted by the network member groups. Of special relevance are: (i) the identification of Toll-like receptor 4 (TLR4) and Type I IFN signalling pathways as determinants of response to IFN-beta; (ii) of novel, highly sensitive IFN-beta bioavailability markers, such as USP18 and HERC; (iii) the finding that Natural Killer (NK) cell maturation is a requisite for clinical response to mitoxantrone, a drug approved for treatment of progressive MS; (iv) that various disease-modifying treatments enhance the modulatory role of CD56bright NK cells in MS; (iv) the identification of Natalizumab-driven changes in the cerebrospinal fluid proteome in MS, and of (v) multi-gene patterns associated with GA and IFN-eta efficacies. Moreover, an extensive validation study is still going on, in which 384 single nucleotide polymorphisms are being genotyped that were selected on the basis of 2 recent pharmacogenomics/IFN-eta genome-wide association studies and of our current understanding of biological pathways involved in IFN-eta response. This is done in 1050 MS patients. Thus, UEPHA-MS has generated a significant amount of new foreground data on drug response biomarkers and several new patent applications are in process. However, for the successful implementation of patient monitoring in clinical practice through biomarkers, availability of pharmacogenomic biomarkers only is unlikely to be sufficient. For instance, specific omics signatures may distinguish a favourable therapeutic response in aggressive MS from a more benign course of disease in non-responders, - a discernment that is difficult to make by clinical measures only. Since MS is a heterogeneous disease, predictive and diagnostic biomarkers are essential to categorize more robustly and more objectively the discrete types and presentations of the disorder. Ultimately, this will generate tangible benefits for MS patients via the precise targeting of novel / existing drugs to biomarker-defined subgroups of patients. In order to achieve progress in this latter categories of biomarkers, UEPHA*MS scientists identified a gene expression pattern that provides an accurate prediction of MS severity in the short-term and that substantiates a role for T and B lymphocyte activation pathways in MS severity. In addition, chitinase 3 like 1 (CHI3L1) was identified as a powerful prognostic biomarker for conversion of patients with clinically isolated syndromes (CIS) to MS. Finally, a novel haplotype of two non-synonymous SNPs at the MS risk locus CD6 was identified that is strongly associated with susceptibility to the disease.
As a training network, UEPHA*MS has been instrumental in training 11 young investigators in cutting-edge technologies for biomarker reseach including omics, cell-based, molecular biology, bioinformatics and systems biology skills. This was accomplished through in–lab training but also via a series of network-wide training courses. UEPHA*MS provided the following network-wide training courses: “Statistical Aspects of Pharmacogenomics Research” (Bilbao, June 2009), and 3 Summer Schools “School 1: Technologies for Biomarker Discovery” (Toulouse, September 2009), “School 2: Systems Biology” (Barcelona, October 2010) and "School 3: The Clinical Validation Process" (Berlin, September 2011), as well as a theoretical / hands-on “Proteomics Workshop” (Rotterdam, March 2010), biotech company visits to Progenika Biopharma and the bio-incubator for biotech start-ups Biokabi followed by an "Outreach" meeting with multiple sclerosis (MS) patients (Bilbao, April 2011). The network activity culminated in a heavily attended conference "Multiple Sclerosis and the Omics Spring" (Bilbao, 15-17 April 2012). Dedicated transferable skills training in in communication skills & ethics, project- and self-management, and entrepreneurship and IPR, were imparted as part of the Summer Schools.
In conclusion, UEPHA*MS has generated significant new knowledge on biomarkers for MS drugs, but also for diagnosis and prognosis. This information will be useful to make patient & drug management and monitoring in MS much more precise and effective.