Novartis’ multiple sclerosis therapy Gilenya was once proposed as a kidney disease treatment because its ability to modulate S1P receptors could theoretically tamp down inflammation. Although that idea didn’t pass the clinical test, the search for better kidney disease drugs targeting the same pathway remains ongoing.
Now, scientists at the University of Virginia found targeting a cellular transporter of S1P, called spinster homolog 2 (Spns2), might be a viable option.
A small-molecule inhibitor of Spns2 suppressed inflammatory signaling in human and mouse kidney cells in lab dishes and reduced kidney fibrosis in mice, the team reported in a new study published in Science Translational Medicine.
The results back Spns2 inhibition as a treatment strategy for chronic kidney disease (CKD) and potentially other inflammatory and fibrotic diseases without causing the side effects associated with systemic modulation of S1P receptors, the researchers wrote in the study.
S1P receptor modulators like Gilenya treat multiple sclerosis by inducing degradation of S1P. Doing so blocks autoreactive immune cells from entering the lymphatic circulatory system and their migrating to inflamed tissues.
The mechanism could theoretically be applied to other autoimmune diseases. But Gilenya failed as an immunosuppressive drug in a phase 3 kidney transplantation trial. The Novartis drug was not only unable to top Roche’s CellCept at preventing transplant rejection, it also caused some increased side effects.
Looking for alternative ways to target S1P, a research team led by the current study’s senior author, Mark Okusa, M.D., previously showed that inhibiting the protein sphingosine kinase 2 (SphK2), which is involved in generating S1P, could block kidney fibrosis in mice.
In the current study, Okusa and colleagues first found that it’s SphK2 in kidney perivascular cells—which line kidney vessels and capillaries—that’s fueling the kidney fibrosis progression. SphK2 enhanced inflammatory signaling in those cells and led to more immune cells infiltrating mice’s kidneys to further promote inflammation, the team found.
S1P is exported outside mice kidney perivascular cells by Spns2 to cause an inflammatory response, the researchers showed. Figuring Spns2 may be a good drug target, the researchers tested an Spns2 inhibitor dubbed SLF1081851.
In both human and mouse kidney perivascular cell cultures, SLF1081851 inhibited S1P export. S1P concentration in the medium decreased after treatment while its concentration inside the cells wasn’t affected.
The drug also outperformed Gilenya in a mouse model of kidney inflammation. Although Gilenya failed to protect the mice from kidney fibrosis, the Spns2 inhibitor did based on the fact that collagen deposition in the kidney decreased and blood creatinine dropped.
While there are ways to treat CKD, there’s still a need for new therapies. Patients can be treated with dialysis. AstraZeneca’s SGLT2 inhibitor Farxiga recently added a CKD indication, and Eli Lilly and Boehringer Ingelheim’s rival drug Jardiance is expected to follow suit.
The FDA also recently approved Bayer’s Kerendia to reduce kidney failure and certain cardiovascular problems in patients with CKD associated with Type 2 diabetes. The drug works by blocking overactivation of the mineralocorticoid receptor, which is thought to contribute to fibrosis and inflammation.
Inflammation is an important component in CKD. Because of SLF1081851’s ability to suppress inflammation in preclinical models, the University of Virginia team suggests targeting Spns2 in the S1P signaling pathway could be a promising strategy to treat kidney fibrosis and other fibrotic conditions.
But as two nephrologists from the University of Texas (UT) noted in an accompanying editorial, future studies should first figure out how to target S1P signaling to the correct cell type to achieve the best therapeutic effect without causing serious side effects.
Okusa and colleagues previously showed that rather than promoting inflammation, S1P signaling in kidney endothelial cells offered protection against inflammation in a mouse model of acute kidney injury. Besides, Spns2 in some brain cells may be essential in maintaining the blood-brain barrier, which keeps toxic materials from entering the brain, the two UT scientists noted.
These findings indicate a need to design cell-specific Spns2 inhibitors, they said. “Future translational work should elucidate how to target sphingosine biology to the correct cell types and signaling pathways.”