Optic neuritis (ON) is an acute autoimmune disease caused by immune attack on the myelin that protects theoptic nerve leading to vision loss. Steroid treatments accelerate recovery of visual acuity in some patients buthave no effect on other visual functions such as contrast sensitivity that are important for activities of daily life.Even with steroid treatments, 13,000 ON patients per year fail to fully recover visual acuity and 50% of ONpatients eventually convert to multiple sclerosis. New therapies are needed to improve ON patient outcomes andquality-of-life. Aberrant activation of T and B lymphocytes drives ON pathologies. Targeting these pathogeniccells is a potential therapeutic strategy. Our company, Trethera, has conducted extensive preclinical studies todevelop a small molecule drug, TRE-515, that has the potential to selectively block lymphocyte activation in ONby inhibiting deoxycytidine kinase (dCK), a key rate-limiting enzyme in the deoxyribonucleoside salvage pathway.Our preliminary studies show (i) that cells of the immune system activate dCK during all phases of disease inthe C57Bl/6 MOG35-55 experimental autoimmune encephalomyelitis (EAE) mouse model of ON, (ii) that TRE-515blocks dCK activity in immune cells in this model, (iii) that TRE-515 blocks phenotypes of CNS demyelination inthis model, (iv) that TRE-515 blocks inflammation of the optic nerve in this model, (v) that TRE-515 blocks T cellactivation in culture, (vi) that TRE-515 blocks B and T cell activation in this model, and (vii) that TRE-515treatments and dCK knockout are not associated with significant toxicities. Collectively, these data stronglysuggest that TRE-515 could be an important new therapy for ON. In support of this, the FDA recently awardedTRE-515 Orphan Drug Status for ON. In the proposed Fast-Track project, we will conduct critical preclinicalstudies to confirm the safety properties of TRE-515 as a therapy for ON, to study the ON disease stage thatTRE-515 affects, to identify the appropriate dosage regimen, and to identify potential biomarkers of targetengagement. In Phase I, we will study whether TRE-515 administered therapeutically can block ON symptoms(Aim 1) and evaluate the genotoxicity of TRE-515 (Aim 2). In Phase II, we will examine the dose-responserelationship between TRE-515 and ON symptoms in the MOG35-55 EAE mouse model of ON (Aim 3), evaluatethe effect of TRE-515 in an additional ON model (Aim 4), study the mechanisms through which TRE-515 blockslymphocyte proliferation (Aim 5), and evaluate whether plasma deoxycytidine and deoxyuridine levels couldserve as biomarkers of TRE-515 target engagement (Aim 6). This IND-enabling work will be critical for movingTRE-515 into the clinical for ON patients and for designing clinical trials with the highest chance of success.
Public Health Relevance Statement: PROJECT NARRATIVE
Optic Neuritis (ON) patients need new, effective, and well-tolerated therapies to improve treatment outcomes
and reduce side effects, and for these patients, reducing aberrant lymphocyte activation with targeted drugs is a
promising therapeutic strategy. Our company, Trethera, is developing a novel small-molecule drug, TRE-515, to
treat ON by targeting a pathway required for lymphocyte activation. In the proposed project, we will conduct
critical preclinical work to further evaluate the safety of TRE-515 as a drug for ON and to further study how TRE-
515 affects ON relevant cells and disease stages.
Project Terms: <2'-deoxy-cytidine><2'-Deoxycytidine Kinase><6-Methylprednisolone><6Alpha-Methylprednisolone> | 