Crohn's disease (CD) is a chronic autoimmune disease in which cells of the immune system attack gut tissueleading to diarrhea, fatigue, pain, and weight loss. CD affects up to one million Americans and is a type ofinflammatory bowel disease. CD is driven by CD4 T cells with a significant role for TH1 and TH17 cells andadditional involvement of B cells. Current therapies for CD can be effective but suffer from high rates of primaryand secondary failure and are associated with significant and sometimes severe side effects. New safe andeffective therapies are needed to treat CD. The deoxyribonucleoside salvage pathway with rate-limiting enzymedeoxycytidine kinase (dCK) salvages extracellular deoxyribonucleosides for intracellular deoxyribonucleotidemetabolism. 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 ofautoimmune diseases including autoimmune hepatitis and multiple sclerosis (MS). One study showed that dCKactivity is upregulated in the spleen in a mouse colitis model at the one time-point analyzed. Trethera has recentlydeveloped TRE-515 as a potent and selective small molecule dCK inhibitor with excellent in vivo pharmacokineticand pharmacodynamic properties. TRE-515 was recently cleared by the FDA (IND# 131939) for investigationaluse in the treatment of solid tumors and has been safely administered to multiple patients in Phase I clinicaltrials. We recently showed in multiple experimental autoimmune encephalomyelitis (EAE) mouse models of MSthat dCK activity is upregulated in lymphocytes during disease, that TRE-515 can limit dCK activity in lymphoidtissues in vivo, that TRE-515 can block clinical MS symptoms in these EAE mouse models when treatments areinitiated at disease induction or at symptoms onset, that TRE-515 limits disease in these models by blockingactivation-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 andproliferating TH1 and TH17 CD4 T cells as a common driver of disease. We hypothesize that TRE-515 could bean effective treatment for CD. We will begin to test this hypothesis in this Phase I STTR grant through thefollowing two aims. Aim 1: To quantify dCK activity in the lymphoid organs and gut throughout disease in theadoptive transfer and SAMP1/YitFc CD models. Aim 2: To test whether the dCK inhibitor TRE-515 blocks diseaseprogression in a preclinical CD model.
Public Health Relevance Statement: PROJECT NARRATIVE
Inflammatory bowel disease is a chronic autoimmune disease characterized by immune attack on the gut.
Current therapies can be effective but suffer from high failure rates and significant side effects, and new therapies
are urgently needed. Here we test whether a newly developed inhibitor of the enzyme deoxycytidine kinase can
limit disease in a mouse model of inflammatory bowel disease.
