Advancing Therapeutic Insights into Hutchinson-Gilford Progeria Syndrome: Current Challenges and Future Directions

Author

Dr. Girendra Kumar Gautam, Rohit Malik, Tinku Kumar


Abstract

 Hutchinson-Gilford Progeria Syndrome (HGPS) is an ultra-rare, usually sporadic genetic disorder characterized by severe growth failure, loss of subcutaneous fat, distinctive craniofacial and skeletal features, and progressive vascular disease that leads to premature death, most often from myocardial infarction or stroke. Classic HGPS is primarily caused by the heterozygous LMNA c.1824C>T variant, which activates a cryptic splice site and generates progerin, a truncated and permanently farnesylated form of prelamin A. Progerin accumulates at the inner nuclear membrane and disrupts nuclear architecture, chromatin organization, DNA repair, mechanotransduction, cellular homeostasis, and vascular function. Although HGPS remains without a definitive cure, therapeutic development has progressed from symptom-directed care to mechanism-based interventions. Farnesyltransferase inhibition with lonafarnib is the established targeted therapy and has demonstrated vascular benefits and an extension of average lifespan. Experimental approaches include antisense oligonucleotides and peptide-conjugated morpholinos that suppress pathogenic LMNA splicing, agents that enhance progerin clearance or autophagy, and genome-editing strategies designed to correct or silence the pathogenic allele. Recent preclinical work also illustrates the potential of precision RNA therapeutics and emerging computational approaches for designing optimized antisense molecules. This review summarizes the molecular basis, clinical phenotype, pharmacological management, investigational therapies, and future research priorities in HGPS, with particular emphasis on translating molecular insights into durable, safe, and accessible treatments.



Keywords

Hutchinson-Gilford Progeria Syndrome; HGPS; LMNA; Progerin; Farnesyltransferase inhibitors; Lonafarnib; Antisense oligonucleotides; Gene editing; CRISPR-Cas; Rare disease; Pharmacology.



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References


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