Development of a Novel, Targeted Small Molecule Inhibitor of the Nucleoside Salvage Pathway to Treat Systemic Lupus Erythematosus

PROJECT SUMMARY Systemic lupus erythematosus (SLE) is a challenging disease in need of new treatment options. SLE is a chronic, debilitating, heterogenous autoimmune disease in which a patient’s immune system attacks vital organs including the kidneys, lung, and brain; leads to fever, stroke, and heart attacks; and causes significant morbidity and mortality. Most patients have low or mild disease that is interspersed with periods of significant disease activity (flares) that cause serious and often permanent organ damage. SLE is driven by autoreactive CD4 T cells (TfH and TH17) and B cells that are activated and proliferate in response to self-antigens. Treatments for SLE can be effective, but only work for a fraction of patients, have a limited duration of response, and carry significant side effects. New therapies are needed to treat SLE, with a particular emphasis on treatments that can induce a remission in a patient experiencing a flare of activity. The deoxyribonucleoside salvage pathway, with rate-limiting enzyme deoxycytidine kinase (dCK), salvages deoxyribonucleoside from extracellular space to provide deoxyribonucleotides for DNA synthesis during rapid cell proliferation as occurs in lymphocytes during a SLE flare. 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 small molecule inhibitor of dCK, with excellent in vivo pharmacokinetics and pharmacodynamics. Currently the drug is 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 using the MRL-Faslpr genetic SLE model, we identified that dCK activity is elevated in the lymph nodes and thymus throughout disease and that TRE-515 can significantly improve various readouts of disease activity when treatments are initiated at symptom onset. 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 results suggest that TRE-515 could represent a novel treatment for SLE, but additional preclinical studies are required. To better understand how TRE-515 could be deployed within the context of such a heterogenous disease as SLE, to identify potential pharmacodynamic biomarkers of response, to increase our confidence that TRE-515 could potentially treat human SLE, and to study how TRE-515 may affect fetal-embryo development as SLE is a disease that often affects young women, we will: Study whether initial dCK activity or TRE-515 target engagement following treatment can predict TRE-515 efficacy in MRL-Faslpr mice (Aim 1). Evaluate TRE-515 efficacy in the adeno-associated virus (AAV)-induced NZB/W SLE model (Aim 2). Determine the effects of TRE- 515 on embryo-fetal development (Aim 3). Results of this work will provide us with a strong foundation from which to pursue clinical trials of TRE-515 in SLE.