Development of a Novel, Targeted Small Molecule Inhibitor of the Nucleoside Salvage Pathway to Treat Systemic Lupus Erythematosus - PROJECT SUMMARY
Lupus is a chronic, systemic autoimmune disease in which cells of the immune system attack organ systems
throughout the body including the kidneys, brain, and lungs and that presents heterogeneously with symptoms
that can include fever, arthritis, alopecia, stroke, and heart attack. Lupus is driven by autoreactive B and CD4 T
cells with a particular role for TfH and TH17 CD4 T cells. Current therapies for lupus can be effective but only
work on a subset of patients, lack biomarkers to resolve the heterogeneity of the disease as it relates to treatment
efficacy, and are associated with significant and sometimes severe side effects. New safe and effective therapies
are needed to treat lupus. The deoxyribonucleoside salvage pathway with rate-limiting enzyme deoxycytidine
(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 lymph nodes in a mouse lupus 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 using [18F]FAC PET, 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 therapeutic efficacy in these models
is associated with a measurable increase in plasma deoxycytidine levels, 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 lupus are different diseases but
share activated and proliferating CD4 T and B cells as a common driver of disease. We hypothesize that TRE-
515 could be an effective treatment for lupus. We will begin to test this hypothesis in this Phase I STTR grant
through two aims. Aim 1: To quantify dCK activity in the lymphoid organs throughout disease using [18F]FAC
PET in a preclinical lupus model. Aim 2: To test whether the dCK inhibitor TRE-515 blocks disease progression
in a lupus model.
