Hutchinson-Gilford Progeria Syndrome: Genetic Insights, Clinical Challenges, and Innovative Therapeutic Approaches

Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare genetic disorder caused by a de novo point mutation in the LMNA gene, resulting in progerin, an abnormal form of lamin A. Progerin disrupts the nuclear architecture, impairs DNA repair, and alters gene expression, collectively leading to systemic premature aging. Diagnosis involves a clinical evaluation, along with genetic and radiological tests, for skeletal and cardiovascular abnormalities. To provide an overview of current and emerging therapeutic strategies for HGPS, with a focus on pharmacological, genetic, and interventional approaches aimed at mitigating disease progression and improving survival outcomes. Current treatment focuses on symptom relief and extending lifespan. Emerging therapies include gene editing, antisense oligonucleotides, ICMT inhibitors, and high-risk cardiovascular interventions. Recent studies highlight angiopoietin-2 as a potential target. Symptomatic management remains the mainstay of care, with lonafarnib, an FDA-approved farnesyltransferase inhibitor, demonstrating modest benefits in reducing progerin accumulation and improving survival. Novel approaches under investigation include gene editing techniques, antisense oligonucleotides, and inhibitors of isoprenylcysteine carboxyl methyltransferase (ICMT). Cardiovascular interventions such as transcatheter aortic valve replacement and ascending aortic constriction are being explored for high-risk patients. Recent studies also identify angiopoietin-2 modulation as a potential therapeutic avenue for vascular and skeletal repair. While lonafarnib provides modest clinical benefit, long-term management of HGPS will likely depend on advances in gene editing, RNA-based therapies, and targeted pharmacological strategies to reduce progerin toxicity. Further research is needed to enhance precision and safety in gene therapies and to explore new molecular targets for broader therapeutic impact.