Friday, November 23, 2012

Pharmacogenomic update on multiple sclerosis: a focus on actual and new therapeutic strategies

Action mechanism of IFN-α/β. (a) The interaction between IFNAR receptor, composed of two subunits IFNAR1 and IFNAR2, and IFN-α/β induces an immediate transcriptional response through JAK–STAT signal transduction pathway. (b) The JAK–STAT system involves a cascade of molecular effectors that includes the membrane receptor, the cytoplasmic JAK and the transcription factors STATs. After signal, JAK autophosporylates itself, then activating STAT proteins. (c) STATs pass from the cytoplasm to the nucleus, promoting transcription of genes responsive to STAT. AAF, IFN-α-activated factor; IFN, interferon; ISRE, IFN-stimulated response elements; JAK, Janus kinase; GAS, IFN-γ-activated sequence; ISGF3, interferon-stimulated gene factor 3; IRF9, interferon regulatory factor 9; STAT, signal transducers and activators of transcription; TYK2, tyrosine kinase 2.
Multiple sclerosis (MS) is an inflammatory and demyelinating disease of central nervous system comprising several subtypes. Pharmacological treatment involves only few drugs. Among these, interferon beta (IFN-β) and glatiramer acetate were the most used. Although evidence supports the efficacy of these agents in treating MS symptoms, actual studies allowed to introduce new innovative drugs in clinical practice. Applying pharmacogenetic approach to MS, IFN-β and several other immune pathways were abundantly investigated. Numerous reports identified some promising therapy markers but only few markers have emerged as clinically useful. This may be partially due to differences in clinical and methodological criteria in the studies. Indeed, responder and non-responder definitions lack standardized clinical definition. The goal of this review is to treat advances in research on the pharmacogenetic markers of MS drugs and to highlight possible correlations between type of responses and genetic profile, with regard to clinical and methodological discrepancies in the studies (Full text).