Targeting deoxycytidine kinase improves symptoms in mouse models of multiple sclerosis

Abstract

Multiple sclerosis (MS) is an autoimmune disease driven by lymphocyte activation against myelin autoantigens in the central nervous system leading to demyelination and neurodegeneration. The deoxyribonucleoside salvage pathway with the rate-limiting enzyme deoxycytidine kinase (dCK) captures extracellular deoxyri-

Targeting host deoxycytidine kinase mitigatesStaphylococcus aureusabscess formation

“…Thus, cohorts of female C57BL/6 mice were treated from day 0 onwards with either vehicle (40% Captisol) or (R)-DI-87 (75 mg/kg) via oral gavage in 12-hour intervals according to a published protocol (Chen et al, 2022a).…”

“…To evaluate the therapeutic value of ( R )-DI-87 in live animals, initial in vivo experiments aimed at analyzing the safety of ( R )-DI-87 in mice following continuous dCK inhibitor treatment. Thus, cohorts of female C57BL/6 mice were treated from day 0 onwards with either vehicle (40% Captisol) or ( R )-DI-87 (75 mg/kg) via oral gavage in 12-hour intervals according to a published protocol (Chen et al, 2022a). On day 16, peripheral blood was collected from both cohorts of mice and subjected to a FACS-based immuno-phenotyping approach (Figure 4A).…”

“…Overall, ( R )-DI-87-mediated inhibition of dCK is a novel host-directed therapeutic concept to mitigate staphylococcal abscess formation in organ tissues upon bloodstream infection. Since ( R )-DI-87 is extremely well tolerated in humans (personal communication; Kenneth A. Schultz, Trethera Corporation, Los Angeles, CA, USA) and currently being investigated in phase I clinical trials for the treatment of non-communicable diseases, including cancer and multiple sclerosis (Poddar et al, 2020; Chen et al, 2022a), this compound already meets the requirements for a prompt launch of clinical studies in individuals that suffer local or invasive staphylococcal infections. Optimization of ( R )-DI-87 or any medically acceptable derivatives thereof may further accelerate this process and concurrently could also aid in the design of pre-exposure prophylactic agents for hospitalized or high-risk patients, with the primary aim to enhance infection control and public health.…”

Oral cytarabine ocfosfate pharmacokinetics and assessment of leukocyte biomarkers in normal dogs

“…As such, therapeutic targeting via the dCK salvage pathway utilizing nucleoside analogs such as Ara‐C or disrupting normal dCK activity is a potent mechanism to inhibit lymphocyte function. Increased dCK activity is reported in several experimental autoimmune models, and inhibiting dCK activity has been shown to ameliorate clinical signs in experimental allergic encephalomyelitis 63 . Saturation‐related parameters for the salvage pathway for Ara‐C, including plasma concentrations and duration of drug exposure, in normal dog leukocytes have not been defined, although maximal Ara‐C concentrations in a majority of pharmacokinetic studies in dogs are in excess of human‐defined saturation concentrations (Table S1).…”

“…Increased dCK activity is reported in several experimental autoimmune models, and inhibiting dCK activity has been shown to ameliorate clinical signs in experimental allergic encephalomyelitis. 63 Saturation-related parameters for the salvage pathway for Ara-C, including plasma concentrations and duration of drug exposure, in normal dog leukocytes have not been defined, although maximal Ara-C concentrations in a majority of pharmacokinetic studies in dogs are in excess of human-defined saturation concentrations (Table S1). [51][52][53][54][55][56][57]64 Clinical response to different Ara-C regimens in dogs with inflammatory brain disease has been reported, and is the ultimate gold standard for efficacy, but reports have been variable with design limitations and contradictory results.…”