Assessing Spns2-dependent S1P Transport as a Prospective Therapeutic Target.

Area of Science:

• Immunology
• Pharmacology
• Drug Discovery

Background:

• Sphingosine 1-phosphate (S1P) receptor modulators (SRMs) treat autoimmune diseases by downregulating lymphocyte S1P receptors, but cause side effects like bradycardia.
• S1P transporters, like spinster homolog 2 (Spns2), provide S1P for lymphocyte receptors, suggesting their inhibition as an alternative therapeutic strategy.
• Spns2 deficiency causes lymphocytopenia and low lymph S1P, indicating the role of Spns2 in immune cell positioning.

Approach:

• Investigated a novel S1P transport blocker (STB), SLF80821178, in rodent models to assess S1P transport inhibition.
• Evaluated SLF80821178's efficacy in a multiple sclerosis model and compared its safety profile to the SRM fingolimod.
• Assessed the impact of chronic SLF80821178 treatment on hearing acuity, a known defect in Spns2 null mice.

Key Points:

• SLF80821178 demonstrated efficacy in a multiple sclerosis model, without the cardiac or lung barrier side effects associated with SRMs.
• Unlike Spns2 null mice, chronic SLF80821178 treatment did not result in hearing defects.
• STB treatment caused a dose-dependent decrease in peripheral blood lymphocytes, serving as a pharmacodynamic marker, but with a maximal reduction (50%) less than SRMs (90%).

Conclusions:

• S1P transport inhibition via STBs offers a potential therapeutic avenue for immune modulation with an improved safety profile compared to SRMs.
• The maximal lymphocyte reduction by STBs is less than SRMs, potentially due to differential effects on T lymphocyte subpopulations.
• Lymph S1P concentrations remained unchanged with STB treatment, suggesting incomplete understanding of S1P transport inhibitor mechanisms.