Biomarkers and therapies associated with Hutchinson-Gilford Progeria Syndrome

Hutchinson-Gilford progeria syndrome (HGPS) is an ultra-rare premature aging disorder caused predominantly by a de novo LMNA c.1824C>T mutation that produces progerin, a truncated and permanently farnesylated lamin A isoform. Progerin accumulation disrupts nuclear lamina integrity and chromatin organization, inducing persistent DNA damage responses, telomere attrition, mitochondrial dysfunction, and cellular senescence. These processes drive a multisystem clinical phenotype characterized by growth impairment, lipodystrophy, musculoskeletal abnormalities, and rapidly progressive vascular disease, with cardiovascular events as the leading cause of mortality. Biomarkers could be used in clinical trials and preclinical models for research purposes. Current candidates span four major categories: (i) molecular markers, including LMNA genotype, progerin levels, γH2AX/pATM signaling, telomere shortening, and epigenetic alterations; (ii) cellular markers reflecting oxidative stress, mitochondrial impairment, and senescence-associated secretory phenotype (SASP); (iii) systemic inflammatory and immune mediators; and (iv) vascular structural and functional indices such as arterial stiffness and endothelial dysfunction, which correlate strongly with survival. Preclinical progeroid mouse models and LMNA-edited minipigs have facilitated translational validation of these biomarker axes. Therapeutic approaches now extend beyond farnesyltransferase inhibition. Lonafarnib improves vascular outcomes and survival; however, persistent cardiovascular decline indicates residual unmet need. Emerging interventions-including mTOR modulation, senolytics, anti-inflammatory agents, metabolic support, antisense oligonucleotides, and gene-editing strategies targeting progerin production-may benefit from biomarker-guided implementation. The integration of multi-parameter biomarker panels with mechanism-based combination therapies represents a promising direction toward precision management in HGPS.