Drug repositioning in SLE: crowd-sourcing, literature-mining and Big Data analysis

Lupus patients are in need of modern drugs to treat specific manifestations of their disease effectively and safely. In the past half century, only one new treatment has been approved by the US Food and Drug Administration (FDA) for systemic lupus erythematosus (SLE). In 2014-2015, the FDA approved 71 new drugs, only one of which targeted a rheumatic disease and none of which was approved for use in SLE. Repositioning/repurposing drugs approved for other diseases using multiple approaches is one possible means to find new treatment options for lupus patients. "Big Data" analysis approaches this challenge from an unbiased standpoint whereas literature mining and crowd sourcing for candidates assessed by the CoLTs (Combined Lupus Treatment Scoring) system provide a hypothesis-based approach to rank potential therapeutic candidates for possible clinical application. Both approaches mitigate risk since the candidates assessed have largely been extensively tested in clinical trials for other indications. The usefulness of a multi-pronged approach to drug repositioning in lupus is highlighted by orthogonal confirmation of hypothesis-based drug repositioning predictions by "Big Data" analysis of differentially expressed genes from lupus patient samples. The goal is to identify novel therapies that have the potential to affect disease processes specifically. Involvement of SLE patients and the scientists that study this disease in thinking about new drugs that may be effective in lupus though crowd-sourcing sites such as LRxL-STAT (www.linkedin.com/in/lrxlstat) is important in stimulating the momentum needed to test these novel drug targets for efficacy in lupus rapidly in small, proof-of-concept trials conducted by LuCIN, the Lupus Clinical Investigators Network (www.linkedin.com/in/lucinstat)

The MS risk allele of CD40 is associated with reduced cell-membrane bound expression in antigen presenting cells: implications for gene function

Human genetic and animal studies have implicated the costimulatory molecule CD40 in the development of multiple sclerosis (MS). We investigated the cell specific gene and protein expression variation controlled by the CD40 genetic variant(s) associated with MS, i.e. the T-allele at rs1883832. Previously we had shown that the risk allele is expressed at a lower level in whole blood, especially in people with MS. Here, we have defined the immune cell subsets responsible for genotype and disease effects on CD40 expression at the mRNA and protein level. In cell subsets in which CD40 is most highly expressed, B lymphocytes and dendritic cells, the MS-associated risk variant is associated with reduced CD40 cell-surface protein expression. In monocytes and dendritic cells, the risk allele additionally reduces the ratio of expression of full-length versus truncated CD40 mRNA, the latter encoding secreted CD40. We additionally show that MS patients, regardless of genotype, express significantly lower levels of CD40 cell-surface protein compared to unaffected controls in B lymphocytes. Thus, both genotype-dependent and independent down-regulation of cell-surface CD40 is a feature of MS. Lower expression of a co-stimulator of T cell activation, CD40, is therefore associated with increased MS risk despite the same CD40 variant being associated with reduced risk of other inflammatory autoimmune diseases. Our results highlight the complexity and likely individuality of autoimmune pathogenesis, and could be consistent with antiviral and/or immunoregulatory functions of CD40 playing an important role in protection from MS