Estimating Daclizumab effects in Multiple Sclerosis using Stochastic Symmetric Nets

Multiple Sclerosis (MS) is an immune-mediated inflammatory disease of the central nervous system which damages the myelin sheath enveloping nerve cells causing severe physical disability in patients. Relapsing Remitting Multiple Sclerosis (RRMS) is one of the most common form of MS and it is characterized by a series of attacks of new or increasing neurologic symptoms, followed by periods of remission. Recently, many treatments were proposed and studied to contrast the RRMS progression. Among these drugs Daclizumab, an antibody tailored against the interleukin −2 receptor of T cells, exhibited promising results. Unfortunately, more recent studies on Daclizumab highlight severe adverse effects, that led to its retirement from the EU marketing authorization process. Motivated by these recent studies, in this paper we describe how computational modelling can be efficiently exploited to improve our understanding on Daclizumab mechanism of action, and on how this mechanism leads towards the observed undesirable effects.

[1]  K. Chu,et al.  New feasible treatment for refractory autoimmune encephalitis: Low-dose interleukin-2 , 2016, Journal of Neuroimmunology.

[2]  Xavier Montalban,et al.  Daclizumab in active relapsing multiple sclerosis (CHOICE study): a phase 2, randomised, double-blind, placebo-controlled, add-on trial with interferon beta , 2010, The Lancet Neurology.

[3]  Placido Bramanti,et al.  Alemtuzumab: a review of efficacy and risks in the treatment of relapsing remitting multiple sclerosis , 2017, Therapeutics and clinical risk management.

[4]  Marco Beccuti,et al.  From Symmetric Nets to Differential Equations exploiting Model Symmetries , 2015, Comput. J..

[5]  Marco Beccuti,et al.  GreatSPN Enhanced with Decision Diagram Data Structures , 2010, Petri Nets.

[6]  Giovanni Chiola,et al.  Stochastic Well-Formed Colored Nets and Symmetric Modeling Applications , 1993, IEEE Trans. Computers.

[7]  Carlo Alberto Artusi,et al.  Natalizumab in Multiple Sclerosis: Long-Term Management , 2017, International journal of molecular sciences.

[8]  A. Saltelli,et al.  Sensitivity analysis for chemical models. , 2005, Chemical reviews.

[9]  D. Kirschner,et al.  A methodology for performing global uncertainty and sensitivity analysis in systems biology. , 2008, Journal of theoretical biology.

[10]  T. Kurtz Strong approximation theorems for density dependent Markov chains , 1978 .

[11]  Marco Ajmone Marsan,et al.  Modelling with Generalized Stochastic Petri Nets , 1995, PERV.

[12]  Abdul Mateen Rajput,et al.  Agent based modeling of Treg-Teff cross regulation in relapsing-remitting multiple sclerosis , 2013, BMC Bioinformatics.

[13]  B. Trapp,et al.  Mechanisms of neuronal dysfunction and degeneration in multiple sclerosis , 2011, Progress in neurobiology.

[14]  Marco Beccuti,et al.  GPU Accelerated Analysis of Treg-Teff Cross Regulation in Relapsing-Remitting Multiple Sclerosis , 2018, Euro-Par Workshops.

[15]  Richard J. Beckman,et al.  A Comparison of Three Methods for Selecting Values of Input Variables in the Analysis of Output From a Computer Code , 2000, Technometrics.

[16]  B. Trapp,et al.  Multiple sclerosis: an immune or neurodegenerative disorder? , 2008, Annual review of neuroscience.

[17]  Peter Sundström,et al.  Rituximab in multiple sclerosis , 2016, Neurology.