Cytomegalovirus (CMV) can cause severe disease and death in infants and immunocompromised people. The first-line drug ganciclovir has high pharmacokinetic variability which leads to significant rates of underexposure or toxicity. Intracellular ganciclovir triphosphate (GCV-TP)─ganciclovir's active anabolite─is associated with concentration-dependent neutropenia, and monitoring could enable dose individualization to improve treatment efficacy. However, GCV-TP is currently measured using liquid chromatography tandem mass spectrometry (LC-MS/MS) which is impractical for routine use, especially in resource-limited settings, due to its high cost, labor-intensiveness, and reliance on specialized equipment. To address this gap, we adapted the REverse transcriptase ACTivity with CRISPR (REACTR) assay to measure GCV-TP. We leveraged previous work using REACTR to measure reverse transcriptase (RT) inhibitors used to treat and prevent human immunodeficiency virus (HIV) because GCV-TP serendipitously inhibits HIV RT. We designed custom DNA templates, primers, and CRISPR complexes to accurately measure GCV-TP spiked into buffer and blood. REACTR reproducibly measured clinically relevant GCV-TP concentrations using a simple workflow and equipment that are readily available in many clinical laboratories. We evaluated the assay's performance with 40 dried blood spots from infants with congenital CMV and REACTR measurements of clinical samples correlated with LC-MS/MS GCV-TP measurements (Spearman ρ = -0.811; p < 0.0001). REACTR correctly identified samples above and below simulated 50% and 75% adherence thresholds with areas under receiver operating characteristic curves (AUCs) of 0.910 and 0.957, respectively. This study highlights the potential of REACTR as a rapid and accessible alternative to LC-MS/MS for therapeutic drug monitoring of GCV-TP.

Treatment options for relapsed or refractory extranodal natural killer/T-cell lymphoma (R/R ENKTL) remain limited. In this phase 1b/2 trial (NCT05464433), we evaluated the safety and efficacy of liposomal mitoxantrone (Lipo-MIT) plus anti-PD-1 tislelizumab in this setting. During dose escalation, patients received Lipo-MIT (16 or 20 mg/m2) plus tislelizumab using a 3 + 3 design, followed by dose expansion at the recommended phase 2 dose (RP2D). The primary endpoint of the dose-escalation phase was dose-limiting toxicities (DLTs), which were assessed to determine the RP2D. The primary efficacy endpoint of the dose-expansion phase was the best complete response (CR) rate. Between July 23 2022 and November 28 2024, 40 patients received study treatment (dose-escalation, n = 6; dose-expansion, n = 34). No DLTs were observed and the RP2D of Lipo-MIT was 20 mg/m2. The prespecified primary efficacy endpoint was met, with a CR rate of 53% (21/40; one-sided 95% lower confidence bound, 38%). The median progression-free survival (secondary endpoint) was 8.2 months (95% confidence interval, 6.1-not estimable) after a median follow-up of 15.3 months. The most common grade ≥ 3 adverse events were leukopenia (53%), neutropenia (40%), and febrile neutropenia (18%). In conclusion, Lipo-MIT plus tislelizumab showed promising anti-tumor activity with an acceptable safety profile in R/R ENKTL.

The rising prevalence of Alzheimer's disease (AD) underscores an urgent need for neuroprotective strategies that modulate cholesterol metabolism, neuroinflammation, improve pathology, and cognitive function. While Liver X receptors (LXRs) and peroxisome proliferator-activated receptors (PPARs) are validated targets for enhancing amyloid-β and tau clearance, clinical translation of first-generation LXR agonists has been hindered by LXRα-mediated hepatic steatosis and hypertriglyceridemia. Here, we report the structure-based design of AU403, a potent, isoform-selective LXRβ/PPARδ dual agonist designed to bypass LXRα-driven hepatotoxicity. Molecular modeling indicates that AU403 achieves LXRβ selectivity by engaging residues Phe329 and Leu330 while avoiding the corresponding LXRα residues Arg305 and Leu316. This structural precision translates to robust functional activity, with luciferase assays confirming potent activation of LXRβ (EC50 ≈ 45 nM) and PPARδ (EC50 ≈ 40 nM). Notably, AU403 exhibits a superior safety profile, circumventing hepatotoxicity, neutropenia, and hERG inhibition that have limited the clinical development of prior agonists. Furthermore, chronic administration of AU403 in 3xTg-AD mice significantly improved cognitive functions and reduced amyloid-β plaque burden, establishing AU403 as a promising dual-acting agonist for the treatment of Alzheimer's Disease.