Small Molecule Inhibition of SLC6A19 for the Treatment of CKD

Background: The SLC6A19 gene encodes the protein BoAT1, a sodium-dependent neutral amino acid transporter expressed on the brush border of the small intestine and proximal tubule of the kidney, where it mediates the uptake of free amino acids and other neutral metabolites. SLC6A19 is a novel target for the treatment of chronic kidney disease (CKD) based on analyses of human data sets that have identified a link between loss of function gene variants with improved renal function and CKD protection. Aristolochic acid (AAI) is a plant-derived nephrotoxin and SLC6A19 loss of function protects against AAI-induced CKD in mice. Methods: To assess whether pharmacological inhibition of SLC6A19 confers protective effects against CKD, we used MZ-402, a potent inhibitor of mouse SLC6A19 (submicromolar IC50 vs leucine uptake in vitro). In mice, acute administration of MZ-402 increases urinary levels of amino acids, confirming target engagement. Results: To enable chronic dosing, MZ-402 was formulated in rodent chow and target engagement was evaluated by urinary glutamine excretion. Glutamine excretion increased 200-fold, similar to that observed in SLC6A19 KO mice. To evaluate the effect of MZ-402, dapagliflozin, and their combination, in AAI-induced nephropathy, C57Bl/6 mice were pretreated with MZ-402 in chow for three weeks prior to AAI challenge. MZ-402 dose-dependently attenuated AAI-induced elevation in the CKD biomarkers uACR, KIM1, and NGAL, and these effects were enhanced in combination with dapagliflozin. Furthermore, in a model of diabetes, chronic inhibition of SLC6A19 decreased blood glucose and enhanced insulin sensitivity. Conclusion: Although the exact mechanisms underlying SLC6A19 are not completely understood, a combination of decreased workload at the proximal tubule, decreased uptake of potential nephrotoxic metabolites, and decreased intraglomerular pressure is proposed. In addition, SLC6A19 inhibition in the intestine may lead to reduced systemic amino acid load that has beneficial effects on whole-body metabolism. These data are in agreement with the protection from CKD observed in humans lacking a functional copy of SLC6A19 and suggest that targeting SLC6A19 is a viable therapeutic option for CKD. Funding: Commercial Support - Maze Therapeutics