In search for better CKD drugs, researchers propose a new-ish target for the disease
19 Aug 2022
In the past few years, three new drugs for CKD have emerged on the market: J&J’s Invokana, AstraZeneca’s Farxiga — both SGLT2 inhibitorsSGLT2 inhibitors — and more recently, Bayer’s Kerendia, a mineralocorticoid receptor antagonist. Notably, Farxiga was approved on the back of a trial that reduced the risk of death for CKD patients — a first for any CKD drug.
However, these new drugs have yet to stop or reverse the disease itself, leaving researchers still searching for better, safer options.
In a study published in
Science Translational Medicine
, scientists from Mark Okusa’s lab at the University of Virginia look at a new target on a previously tried-and-failed pathway, showing that going after the new target reduced kidney injury and scar tissue buildup in mouse models.
Novartis previously tried its multiple sclerosis drug Gilenya for CKD, in hopes it could reduce inflammation and fibrosis associated with the disease, only to see it flunk a Phase III study. Gilenya is an S1P receptor agonist that reduces inflammation by slowing white blood cells from leaving the lymph nodes. Looking at the same pathway, Okusa’s lab previously showed that deleting a gene that codes for a protein needed to make S1P in mice protected them from kidney tissue scarring.
In this study, Okusa’s lab followed up on that finding. They observed that when S1P, a signaling molecule implicated in cell migration among other processes, was transported out of kidney cells through a transporter dubbed Spns2, there were increased amounts of inflammatory cytokines, immune cell activity, and fibrosis in both cell and mouse models.
So the researchers created an Spns2 inhibitor to prevent that S1P transport out of the kidney cells. In cells, that inhibitor successfully reduced inflammatory cytokines, and in mice, it reduced the degree of kidney fibrosis. In another mouse experiment, the researchers compared their inhibitor to Gilenya and found that, unlike Gilenya, their inhibitor protected against kidney fibrosis.
“Targeting this S1P signaling pathway, enabling control of S1P concentrations in the local microenvironment, is a promising strategy for the treatment of kidney fibrosis and potentially other inflammatory and fibrotic diseases that can perhaps avoid the adverse events associated with systemic modulation of S1P receptors,” the researchers wrote in the study.
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