Nat. Commun. | 药物筛选联合机器学习发现儿童痴呆潜在神经保护药物

TL;DR - A Nature Communications study combined patient-derived iPSC neural cultures, high-content drug screening, machine learning, transcriptomics, and electrophysiology to identify potential repurposed treatments for MPS IIIA childhood dementia. It found nine neuroprotective candidates, but the evidence remains preclinical and in vitro.

• Models derived from five patients reproduced heparan sulfate accumulation, lysosomal abnormalities, neuronal death, reactive astrocytosis, and dysfunctional neural-network activity.
• XGBoost and CNN models classified drug-treated cells as “healthy-like” or “MPS IIIA-like,” largely agreeing with conventional phenotypic screening of 63 compounds.
• Nine drugs improved disease-associated phenotypes across multiple analyses, including acetyl-D-leucine, allopurinol, deferoxamine, hydroxychloroquine, lithium, probenecid, and theophylline.
• Allopurinol–probenecid and four-drug combination treatments produced neural-network improvements that persisted for two weeks after withdrawal, warranting further dose, safety, blood-brain-barrier, and in vivo studies.