Research & Development
Novel, human genetics-based discoveries.
We leverage the power of human genetic diversity to develop life-transforming therapies. In partnership with communities around the world, we characterize novel genetic associations to disease. Studies are powered to identify broad disease-relevant phenotypes, with particular focus on fibrotic, inflammatory, liver, and kidney diseases. Targets with strong human genetics are at the foundation of our biology and drug discovery pipeline.
- Chronic Kidney Disease
- Inflammatory Kidney Disease
- Type 2 Diabetes
Chronic Kidney Disease Target
We have identified a genetic locus that is associated with worsening kidney function and urinary metabolites. Kidney expression and metabolomic studies confirmed overactivity of the protein in individuals with worse kidney phenotypes. Translational biology studies have demonstrated that inhibition or knock-out of the protein results in protection from damage in a 3D kidney tubule system, as well as in kidney disease rodent models. These data suggest inhibition of the protein may offer therapeutic potential for chronic kidney diseases (CKD). Efforts are underway to identify suitable small molecule inhibitors, with the goal of nominating a development candidate for IND-enabling studies.
Inflammatory Kidney Disease Target
Based on an early partnership, we identified a loss-of-function genetic variant that is over 1,200-times more frequent in the participating community as compared to global genetic references. Phenotypic studies demonstrated an association between the variant and end-stage renal disease, with individuals lacking the protein exhibiting a higher disease risk. In cellular models, we demonstrated a role for this protein as a regulator of immunity and inflammation, inhibiting T-cell activation, proliferation, and cytokine-release. Efforts are focused on identifying the T-cell receptors for this protein, and exploring various preclinical models to better characterize the role of the protein in kidney, immune, and inflammatory functions.
Type 2 Diabetes Target
We characterized a novel loss-of-function variant that is strongly associated with Type 2 Diabetes (T2D). This variant was found to be 1,500-times more frequent in the participating community as compared to global genetic references. We initiated translational biology efforts by confirming expression in the pancreas, including in beta-islet cells at the gene and protein level. Using a human beta-islet cell line assay, we reduced expression of the protein using siRNA and demonstrated a significant decrease in insulin secretion upon glucose stimulation without impacting cell survival. This provides a mechanistic link back to the genetic-phenotypic finding and a novel therapeutic pathway for improving insulin secretion in patients with diabetes.
A genetic locus was identified that associates with age of onset of a specific type of inflammatory disease, as well as with a metabolite that implicates the inflammasome. Together, these data indicate a novel point of intervention in immune-related dysfunction. Work is ongoing to explore the biology of this particular gene, and to more broadly explore modulators of inflammation-related pathways using a genome-wide CRISPR screening approach.