De novo pathogenic variants in GNAO1-the gene encoding the major neuronal G protein Gαo-cause pediatric encephalopathies and other neurological deficiencies largely refractory to available therapies. Zn2+ emerged to restore guanosine triphosphate hydrolysis and cellular interactions of pathogenic Gαo; dietary zinc salt supplementation improves lifespan and motoric function in a Drosophila disease model. Using biochemical, animal, and first-in-human studies, we provide support for the patient stratification and application of zinc acetate in GNAO1-associated disorders. We show that 16 different pathogenic missense variants cluster in three distinct groups in their responsiveness to Zn2+, and we provide the safety study in a mouse disease model. We further describe treatment of a 3-year-old patient with the common pathogenic GNAO1 variant c607G>A, p.Gly203Arg with oral 50mg zinc (in the form of zinc acetate) daily, as applied in Wilson's disease. During 11months of treatment, the patient shows cessation of daily dyskinetic crises, improved Burke-Fahn Marsden Dystonia Rating Scale movement score, reduction in epileptic seizures, and an excellent safety profile. Our findings warrant a large-scale clinical trial and might set the new standard of care for GNAO1-related disorders. This work was funded by the Russian Science Foundation (grant #21-15-00138) and GNAO1 España.

Organoids are three-dimensional (3D) cultures, normally derived from stem cells, that replicate the complex structure and function of human tissues. They offer a physiologically relevant model to address important questions in cancer research. The generation of patient-derived organoids (PDOs) from various human cancers allows for deeper insights into tumor heterogeneity and spatial organization. Additionally, interrogating non-tumor stromal cells increases the relevance in studying the tumor microenvironment, thereby enhancing the relevance of PDOs in personalized medicine. PDOs mark a significant advancement in cancer research and patient care, signifying a shift toward more innovative and patient-centric approaches. This review covers aspects of PDO cultures to address the modeling of the tumor microenvironment, including extracellular matrices, air-liquid interface and microfluidic cultures, and organ-on-chip. Specifically, the role of PDOs as preclinical models in gene editing, molecular profiling, drug testing, and biomarker discovery and their potential for guiding personalized treatment in clinical practice are discussed.

Clinical management and therapeutics development for Alzheimer's disease (AD) have entered a new era, with recent approvals of monoclonal antibody therapies targeting the underlying pathophysiology of the disease and modifying its trajectory. Imaging and fluid biomarkers are becoming increasingly important in the clinical development of AD therapeutics. This review focuses on the evidence of fluid biomarkers from recent amyloid-β-targeting clinical trials, summarizing biomarker data across 12 trials. It further proposes a simple framework to put biomarker guidance in the context of amyloid-pathway-targeted disease modification, delineates factors that impact biomarker data in clinical trials, and highlights knowledge gaps and future directions. Increased knowledge and data on biomarkers in the context of disease progression and disease modification will help to better design future AD trials and guide the clinical management of patients on AD-modifying therapies, bringing us closer to the implementation of precision medicine in AD.