Objective
To learn whether our S1P transport inhibitors block the onset of T1D in a pre-clinical mouse mode and to compare the immune responses to infection and vaccination in mice treated with S1P transport inhibitors and S1P receptor modulators.
Background Rationale
Study of an experimental immunosuppressive drug, FTY720, revealed that this drug is important for normal lymphocyte trafficking in and out of the bloodstream. Eventually, FTY720 (renamed fingolimod) was approved as a drug to treat multiple sclerosis. Fingolimod works very well in preventing overt diabetes mellitus (DM) in the standard pre-clinical (mouse) model of T1D but, unfortunately, the drugs in the fingolimod class (there are 5 now) are too broadly immunosuppressive to be used in T1D patients. We are working with S1P transporters, which are ‘next door’ to the target of fingolimod in the S1P pathway (i.e., S1P receptors on the surface of white blood cells). S1P transport inhibitors also modulate immune cell trafficking but are these are less disruptive than fingolimod-type drugs. We want to know both whether S1P transport inhibitors work as well as fingolimod in the standard pre-clinical T1D model and how much less immunosuppressive S1P transport inhibitors are than SRM drugs.
Description of Project
Type 1 diabetes (T1D) is an autoimmune disease characterized by the immune system eliminating the insulin producing cells ('beta cells’) of the pancreas. Normally, these cells detect the amount of blood glucose and release the correct amount of insulin to control changes in blood glucose that follow eating. Lacking beta cells, the T1D patient must monitor blood glucose measurements and injection insulin. Although advances in ‘artificial pancreas’ devices have eased the burden on patients, these devices only approximate the exquisite glucose control of the beta cells. Thus, safe drugs for prolonging beta cell function are needed.
Anticipated Outcome
Based on results of our studies comparing fingolimod and S1P transport inhibitors in models of multiple sclerosis, we expect that S1P transporters will, like fingolimod, be effective in models of T1D. Further, the effects of fingolimod and an S1P transport inhibitor on white blood cell counts are quantitatively different. Thus, we expect that S1P transport inhibitors will be significantly less immunosuppressive than S1P receptor modulator drugs such as fingolimod.
Relevance to T1D
T1D is the result of an assault by the immune system on the beta cells of the endocrine pancreas. There are two points in the disease process that are amenable to therapy with an immunomodulating drug. One is enabled by the advent of screening to identify patients in the prodromal stage (Stage 2) and the other is with newly diagnosed T1D patients who temporarily (3-12 months (“honeymoon period”)) have normal blood glucose without injecting insulin. An immunomodulatory drug that prevents, or even significantly delays, the onset of overt diabetes and/or significantly prolongs remission in newly diagnosed T1D patients is needed. S1P transport inhibitors might be such a drug class.