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In this paper we present a robust methodology to deal with phenotype prediction problems associated to drug repositioning in rare diseases, which is based on the robust sampling of altered pathways. We show the application to the analysis of IBM (Inclusion Body Myositis) providing new insights about the mechanisms involved in its development: cytotoxic CD8 T cell-mediated immune response and pathogenic protein accumulation in myofibrils related to the proteasome inhibition. The originality of this methodology consists of performing a robust and deep sampling of the altered pathways and relating these results to possible compounds via the connectivity map paradigm. The methodology is particularly well-suited for the case of rare diseases where few genetic samples are at disposal. We believe that this method for drug optimization is more effective and complementary to the target centric approach that loses efficacy due to a poor understanding of the disease mechanisms to establish an optimum mechanism of action (MoA) in the designed drugs. However, the efficacy of the list of drugs and gene targets provided by this approach should be preclinically validated and clinically tested. This methodology can be easily adapted to other rare and non-rare diseases.

Robust Sampling of Altered Pathways for Drug Repositioning Reveals Promising Novel Therapeutics for Inclusion Body Myositis