ハッチンソン・ギルフォード症候群

[This corrects the article DOI: 10.3389/fphys.2025.1599339.].

BACKGROUND: Progeroid laminopathies (PLs), including Hutchinson-Gilford progeria syndrome (HGPS), are rare premature aging disorders in which cardiovascular complications drive early mortality. Antisense oligonucleotides (ASOs) represent a promising therapeutic strategy, yet optimal design principles and their impact on cardiovascular pathology remain insufficiently defined. METHODS: We developed an AI-driven pipeline to design ASOs targeting the 3'UTR of LMNA transcripts to suppress processing-deficient pathogenic lamin A isoforms. Lead candidates were evaluated in patient-derived induced pluripotent stem cell-derived cardiomyocytes (PL-iCMs), 3D cardiac organoids, and LMNA transgenic mouse models. Efficacy, toxicity, and systemic transcriptional responses were assessed using molecular, histological, and serum biochemical analyses. FINDINGS: The optimized ASO, LM2556, selectively reduced progerin and farnesylated pre-lamin A expression while preserving lamin C. LM2556 mitigated cellular senescence and improved structural and functional phenotypes in PL-iCMs and cardiac organoids. In vivo, LM2556 decreased pathogenic lamin A isoforms across multiple tissues without evidence of hepatotoxicity or nephrotoxicity. Long-term administration ameliorated progeroid features, improved cardiovascular pathology, extended median lifespan by 82.86%, and enhanced overall healthspan in LMNA transgenic mice. CONCLUSIONS: These findings establish an AI-based framework for therapeutic ASO design and provide proof-of-concept evidence that targeting the 3'UTR of LMNA transcripts can effectively suppress pathogenic lamin A isoforms and ameliorate systemic progeroid phenotypes. FUNDING: This work was funded by the National Natural Science Foundation of China (82450116 and 82502251).

Centenarians represent a natural model of delayed human aging, offering a unique opportunity to uncover genetic mechanisms that promote longevity. However, the functional consequences of the genetics variants carried by these long-lived individuals remain poorly characterized in physiologically relevant systems. Here, we introduced two linked missense variants in SIRT6 enriched in Ashkenazi Jewish centenarians into the endogenous SIRT6 locus of human embryonic stem cells and differentiated them into somatic lineages to define their effects in a native genomic context. We revealed that centenarian variants elevated endogenous SIRT6 protein abundance through weakened interaction with vimentin, and altered endogenous SIRT6 enzymatic activities, including enhanced mono-ADP-ribosyltransferase activity and reduced deacetylase activity. Functionally, these variants delayed replicative senescence and conferred resistance to progerin-induced stress, accompanied by preservation of DNA repair gene expression programs and suppression of transposable element derepression. Guided by these findings, we evaluated the translational potential of both genetic and pharmacological interventions, demonstrating that adeno-associated virus (AAV)-mediated delivery of centenarian SIRT6 or pharmacological activation of SIRT6 using fucoidan from Fucus vesiculosus (Fucoidan-FV) partially attenuated aging-associated molecular defects, including genome instability and LINE1 derepression, in progeria fibroblasts. Together, these findings demonstrate that centenarian variants exert multifaceted effects on SIRT6 function to enhance cellular stress resistance, and providing a framework for translating genetic discoveries from long-lived individuals into mechanistic insight and potential gerotherapeutic strategies for healthy aging.