GM-CSF targeted therapy for Crohn’s Disease.

Personalized treatment based on individual mutations: GM-CSF targeted therapy for Crohn’s Disease

The current treatment for Crohn’s Disease (CD) is heavily focused on suppressing the adaptive immune response to relieve inflammation. Our work on the CSF2RB mutation in the Ashkenazi Jewish population challenges that concept and provides genetic and functional data to support the theory that susceptibility to CD comes from defects of the innate immune response against commensal bacteria. Our work was published in the leading journal in the field of Gastroenterology.

After sequencing DNA of approximately 1,500 unrelated affected individuals and 2,500 unaffected Ashkenazi Jewish individuals, we narrowed in on the genetic variant in the CSF2RB gene. This variant was found in approximately 4% of healthy Ashkenazi individuals but in approximately 6% of those with CD. CSF2RB is the receptor of granulocyte-macrophage colony stimulating factor (GM-CSF). We first demonstrated that GM-CSF signaling play a crucial role in maintaining gut homeostasis. We further undertook functional experiments to elucidate the impact, at a cellular level, of this mutation. With cell line data and monocytes from CD patients with this mutation, our data showed reduced cellular responses to stimulation by GM-CSF.

Our work shows the role of CM-CSF/CSF2RB signaling in the pathogenesis of CD. Moreover, the CD patients carrying this mutation are the best candidates for GM-CSF targeted therapy. The findings that we presented will likely be of broad interest and have the potential to shift the focus of the field from adaptive to innate immunity in CD pathogenesis. This is a novel prospect in the era of personalized medicine: to personalize treatment based on individual mutations.