Editors' ChoiceHuman Genetics

RA-cing Toward Drugs from a Genetics Starting Line

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Science Translational Medicine  19 Jun 2013:
Vol. 5, Issue 190, pp. 190ec102
DOI: 10.1126/scitranslmed.3006750

For translational scientists, a metaphorical checkered flag has been waved: the myriad genetic loci associated with human diseases. The race is on to unearth disrupted genes, pathways, and mechanisms of action associated with risk-conferring genetic variants, particularly for diseases with few treatment options. A new report by Li et al. describes the translational sprint from an association between rheumatoid arthritis (RA) and a variant at the CD40 gene to high-throughput screening for small-molecule RA therapeutics.

The investigators began with systematic genotyping to fine-map the CD40 association in >20,000 individuals to identify the causal mutation responsible for the association signal. These results were jointly interpreted with additional flow-cytometry experiments so as to reveal a gain-of-function mechanism for a leading variant, in which the allele that predisposes people to RA correlated with higher CD40 expression on the surface of primary human CD19+ B cells. B cells are linked to the pathogenicity of RA, and CD19 expression is the earliest hallmark of the B cell lineage. In a human B cell line (BL2), the elevated CD40 on the surface of these cells increased activation of the inflammatory nuclear factor–κB (NF-κB) pathway, revealing a potential pathogenic mechanism for the disease. The authors then optimized a high-throughput, NF-κB−driven luciferase reporter screen to test the effects of >2200 chemical compounds on CD40 pathway activity. Twenty of the identified candidate compounds—some known and some new—were shown, in secondary screens to be BL2 cell viable, dose-dependent inhibitors of the CD40 pathway at concentrations potentially reasonable for a lead compound. Two known and two new compounds were selected for further testing, which revealed that all four inhibited CD40-mediated NF-κB signaling in primary CD19+ B cells collected from healthy control donors.

More research is needed (such as target identification and animal model) to assess whether these promising compounds will proceed to clinical trials. But the authors have designed a model “race track” that may inspire other researchers to run their best candidate mutations toward the drug-discovery finish line.

G. Li et al. Human genetics in rheumatoid arthritis guides a high-throughput drug screen of the CD40 signaling pathway. PLoS Genet. 9, e1003487 (2013). [Full Text]

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