Project Grant R42DK138578

DEVELOPMENT OF A NOVEL, TARGETED SMALL MOLECULE INHIBITOR OF THE NUCLEOSIDE SALVAGE PATHWAY TO TREAT CROHN'S DISEASE - 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, WEIGHT LOSS, FISTULAS, AND AN INCREASED RISK OF COLORECTAL CANCER. CD AFFECTS UP TO ONE MILLION AMERICANS AND IS A TYPE OF INFLAMMATORY BOWEL DISEASE (IBD). 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 DEOXYRIBONUCLEOSIDES FROM EXTRACELLULAR SPACE TO PROVIDE DEOXYRIBONUCLEOTIDES FOR DNA SYNTHESIS DURING RAPID CELL PROLIFERATION AS OCCURS IN LYMPHOCYTES DURING CD. 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 ENRICHED IN LYMPHOID ORGANS IN MICE AND HUMANS, IS ACTIVATED IN LYMPHOCYTES DURING PERIODS OF DISEASE IN MODELS OF AUTOIMMUNITY, BUT IS NOT REQUIRED FOR NORMAL HEALTHY CELLS. TRETHERA HAS DEVELOPED TRE-515, A FIRST-IN-CLASS SMALL MOLECULE INHIBITOR OF DCK, WITH EXCELLENT IN VIVO PHARMACOKINETICS AND PHARMACODYNAMICS THAT IS CURRENTLY IN PHASE 1 CLINICAL TRIALS FOR THE TREATMENT OF SOLID TUMORS WHERE IT IS SHOWING MILD SIDE EFFECTS AND SIGNS OF EFFICACY. IN PREVIOUS WORK IN THE ADOPTIVE CD4 T CELL TRANSFER (ACT) MODEL OF IBD, WE SHOWED THAT DCK ACTIVITY IS UPREGULATED IN THE MESENTERIC LYMPH NODES DURING DISEASE AND CORRELATES WITH DISEASE ACTIVITY. TREATING ACT IBD MICE WITH TRE-515 STARTING AT SYMPTOM ONSET LED TO A SIGNIFICANT IMPROVEMENT IN THE GUT LENGTH-TO-WEIGHT RATIO (A MEASURE OF DISEASE ACTIVITY) AND A DECREASE IN HISTOLOGICAL MEASURES OF DISEASE INCLUDING INFLAMMATION, GLAND LOSS, AND EDEMA. MECHANISTICALLY, TRE-515 DECREASED THE LEVELS OF ACTIVATED AND EFFECTOR MEMORY CD4+ T CELLS IN THE MESENTERIC LYMPH NODES. IN THIS STUDY, TRE-515 WAS AS EFFECTIVE AT TREATING IBD SYMPTOMS AS STANDARD-OF-CARE COMPARATOR ANTI-IL-12/IL-23. THIS WORK BUILDS ON STUDIES SHOWING THAT TRE-515 CAN LIMIT DISEASE IN MODELS OF OTHER AUTOIMMUNE DISEASES INCLUDING THE EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS MOUSE MODEL OF MULTIPLE SCLEROSIS AND OPTIC NEURITIS. THESE DATA STRONGLY SUGGEST THAT TRE-515 COULD REPRESENT A NOVEL, SAFE, AND EFFECTIVE TREATMENT FOR CD. HOWEVER, ADDITIONAL PRECLINICAL STUDIES ARE REQUIRED INCLUDING FURTHER WORK TO DEFINE THE MECHANISMS THROUGH WHICH TRE-515 LIMITS DISEASE IN THE ACT IBD MODEL AS WELL AS CRITICAL EFFICACY STUDIES IN A SEPARATE, CD-SPECIFIC MOUSE MODEL THAT INCORPORATES ADDITIONAL ASPECTS OF CD NOT PRESENT IN THE ACT IBD MODEL. AIM 1: TO FURTHER STUDY HOW RAPIDLY TRE-515 WITH A UNIQUE MECHANISM OF ACTION BLOCKS DISEASE PROMOTING IMMUNE CELLS IN THE ACT IBD MODEL AND COMPARES TO STANDARD OF CARE. AIM 2: TO QUANTIFY DCK ACTIVITY IN THE LYMPHOID ORGANS THROUGHOUT DISEASE IN THE SAMP1/YITFC CD MOUSE MODEL. AIM 3: TO TEST IF TRE-515 BLOCKS IMMUNE ACTIVATION REPRESENTATIVE OF A CD FLARE IN SAMP1/YITFC MICE.