Astellas Pharma (Japan)

The Multi-Attribute Method (MAM) using liquid chromatography/mass spectrometry (LC/MS) is widely applied to evaluate post-translational modifications (PTMs) in antibody therapeutics. This approach allows the monitoring of multiple PTMs within a single method. In this study, we extended the scope of MAM by incorporating host cell proteins (HCPs) as additional targets and developed a dual, integrated PTMs-HCPs MAM platform. This platform enables the simultaneous evaluation of more comprehensive critical quality attributes through a combination of MS1-based PTMs analysis and data-independent acquisition-based HCP quantification. Although proteomics-based characterization of residual HCPs has been extensively reported, prior studies have primarily focused on purified drug substances or products. Here, we demonstrate the application of our integrated platform to unpurified bulk harvest samples, eliminating the need for purification. While conventional PTMs-MAM and HCP-proteomics are typically conducted separately on purified samples, our dual integrated-MAM approach allows the linking of antibody PTMs with their potential HCP influencers within a single LC/MS injection.

We propose a low-cost method for precise position and attitude estimation in large-scale LEO satellite formations. In our approach, anchor satellites equipped with ToF cameras capture point cloud data from nearby satellites and apply a template matching technique using an efficient 3D template model. Hardware experiments achieved a position error of less than 8 mm. A total of 217 satellites were processed in 6.5 seconds on a Raspberry Pi 4, demonstrating computational and power efficiency suitable for in-flight operation.

mRNA therapeutics represent a relatively new therapeutic modality with the potential for a diverse range of clinical applications, from vaccines to regenerative therapy. Recent clinical advances in mRNA-based vaccines have revealed that the inflammatory nature of lipid nanoparticle (LNP) formulations leads to acute side effects and plays an important adjuvant role in enhancing efficacy (i.e., immunogenicity). Therefore, understanding the biological responses associated with LNP formulations is broadly interesting for further advancing the therapeutic application of the mRNA platform while ensuring safety and efficacy. Here, we report that an intramuscularly administered firefly luciferase (Fluc) mRNA/LNP formulation enhanced proinflammatory responses, characterized by upregulation of proinflammatory chemokine expression and local leukocyte infiltration. Furthermore, in a mouse hindlimb ischemia (HLI) model, this mRNA/LNP formulation induced blood flow recovery without mRNA encoding any pro-angiogenic gene. In an attempt to mitigate the immune response, we employed severely immunocompromised NSG mice, which exhibit multiple defects in host immunity, as an HLI model and demonstrated that the mRNA/LNP formulation was unable to induce blood flow recovery in this condition. These findings suggest that the mRNA/LNP formulation can be the primary substance in enhancing the blood flow recovery after ischemia through immune activation.

ZIP14/SLC39A14, a membrane-bound metal transporter, is essential for systemic metal homeostasis and has been implicated in inflammatory and metabolic disorders, including cancer-associated cachexia. Despite its biological and therapeutic significance, no selective inhibitors have been identified. Here, we identify 1-phenyl-8-(2-phenylethyl)-1,3,8-triazaspiro[4.5]decan-4-one (PPTD) as the first selective small-molecule inhibitor of ZIP14. PPTD efficiently blocks ZIP14-mediated uptake of zinc, iron, manganese, and cadmium, while sparing the closely related transporter ZIP8/SLC39A8. Mechanistically, PPTD binds specifically to a pocket formed at the dimer interface of ZIP14, as revealed by AlphaFold3 structural prediction, ligand-interaction profiling, structure-activity analyses, and site-directed mutagenesis, providing direct evidence for a targeted inhibition mechanism. ZIP14-driven metal influx promotes reactive oxygen species and lipid peroxidation, leading to cytotoxicity, which PPTD effectively reverses. In vivo , PPTD ameliorates major features of cancer cachexia in mice, including weight loss, reduced survival, muscle wasting, impaired locomotor activity, and disease progression. PPTD thus provides both a chemical probe to dissect ZIP14 function and a potential therapeutic candidate for cancer cachexia, establishing a foundation for the development of therapies targeting ZIP14-mediated metal dysregulation.

Background: Mismatch negativity (MMN) is a component of the auditory event-related potential (ERP) that is elicited during a passive oddball paradigm where task-irrelevant infrequent deviants are presented in a stream of more frequent standard stimuli. MMN is believed to index a pre-attentive stage of auditory information processing closely linked to N-methyl-D-aspartate receptors (NMDAR). Ketamine is thought to act primarily as an NMDAR antagonist, has been used in clinical trials to model the symptoms of schizophrenia and is increasingly used in the clinic to treat depression. Various studies have reported that ketamine reduces MMN amplitude which, in turn, might reflect reduced function of NMDAR-mediated neurotransmission. Nonetheless, there is growing evidence showing MMN amplitude either having high variability or, paradoxically, moving in the opposite direction after ketamine in different individuals. Methods: In here, we analyzed results from three independent ERP studies to test the hypothesis of a cross-over interaction (″disordinal″ drug effect) between the duration-deviant MMN at baseline (without ketamine) and the direction and magnitude of the ketamine effect. To rule out regression to the mean (RTM), a statistical phenomenon that may also partially explain this cross-over interaction, we separately estimated RTM using a drug-free test-retest study. Results: Our results are the first to statistically demonstrate the existence of a disordinal drug response to ketamine, where the direction and magnitude of ketamine-induced changes in MMN amplitude can be predicted by baseline MMN amplitude. Conclusions: These new insights may contribute to novel precision medicine approaches to treatment of CNS disorders.

Inherited and complex retinal degenerative diseases, such as retinitis pigmentosa, age-related macular degeneration, and glaucoma, represent a significant global burden of irreversible vision loss. Due to immense genetic and clinical heterogeneity and complex underlyingmechanisms, these diseases still lack safe and effective disease-modifying treatments. This review summarizes the current landscape of gene therapeutic approaches to develop novel treatments for these blinding conditions. Specifically, we provide an update on several ongoing or completed clinical trials on gene-specific or gene-agnostic approaches, including recombinant adeno-associated viral vector-mediated delivery of the full gene or gene editing and antisense oligonucleotide components into the eye. We also discuss the initial clinical trial results of the use of the different approaches to ocular delivery, including subretinal, intravitreal, and suprachoroidal delivery. While long-term clinical trial data and refined clinical endpoints are essential to assess the efficacy, safety, and durability of these strategies, the data so far underscore the immense potential of gene therapy to revolutionize the management of retinal diseases in patients living with these debilitating conditions.