Development of a Novel, Targeted Small Molecule Inhibitor of the Nucleoside Salvage Pathway to Treat Crohn's disease

点击翻译按钮获取中文摘要

PROJECT SUMMARY Crohn’s disease (CD) is a chronic autoimmune disease in which cells of the immune system attack gut tissue leading to diarrhea, fatigue, pain, and weight loss. CD affects up to one million Americans and is a type of inflammatory bowel disease. CD is driven by CD4 T cells with a significant role for TH1 and TH17 cells and additional involvement of B cells. Current therapies for CD can be effective but suffer from high rates of primary and secondary failure and are associated with significant and sometimes severe side effects. New safe and effective therapies are needed to treat CD. The deoxyribonucleoside salvage pathway with rate-limiting enzyme deoxycytidine kinase (dCK) salvages extracellular deoxyribonucleosides for intracellular deoxyribonucleotide metabolism. dCK activity can be measured non-invasively in vivo in mice and humans using the PET radiotracers [18F]FAC and [18F]CFA, respectively. dCK activity is upregulated in lymphocytes in multiple preclinical models of autoimmune diseases including autoimmune hepatitis and multiple sclerosis (MS). One study showed that dCK activity is upregulated in the spleen in a mouse colitis model at the one time-point analyzed. Trethera has recently developed TRE-515 as a potent and selective small molecule dCK inhibitor with excellent in vivo pharmacokinetic and pharmacodynamic properties. TRE-515 was recently cleared by the FDA (IND# 131939) for investigational use in the treatment of solid tumors and has been safely administered to multiple patients in Phase I clinical trials. We recently showed in multiple experimental autoimmune encephalomyelitis (EAE) mouse models of MS that dCK activity is upregulated in lymphocytes during disease, that TRE-515 can limit dCK activity in lymphoid tissues in vivo, that TRE-515 can block clinical MS symptoms in these EAE mouse models when treatments are initiated at disease induction or at symptoms onset, that TRE-515 limits disease in these models by blocking activation-induced T and B cell proliferation without affecting other cells in the immune system, and that TRE- 515 directly blocks T cell proliferation in culture. MS and CD are different diseases but share activated and proliferating TH1 and TH17 CD4 T cells as a common driver of disease. We hypothesize that TRE-515 could be an effective treatment for CD. We will begin to test this hypothesis in this Phase I STTR grant through the following two aims. Aim 1: To quantify dCK activity in the lymphoid organs and gut throughout disease in the adoptive transfer and SAMP1/YitFc CD models. Aim 2: To test whether the dCK inhibitor TRE-515 blocks disease progression in a preclinical CD model.