Assessing the Efficacy of Small Molecule Drugs in Hutchinson-Gilford Progeria Syndrome: A Review of Clinical Trials.

Abstract

Hutchinson-Gilford Progeria Syndrome (HGPS), or progeria, is an exceptionally rare disorder characterized by premature aging. It is primarily caused by a c.1824C>T point mutation in exon 11 of the LMNA gene, though other rare pathogenic variants have also been reported. This mutation leads to aberrant splicing, producing a farnesylated mutant form of lamin A known as progerin. Progerin accumulates abnormally in the nuclear lamina, triggering numerous cellular dysfunctions, including nuclear deformation, disrupted proteostasis, endoplasmic reticulum (ER) stress, replicative stress, increased reactive oxygen species (ROS) production, impaired DNA endjoining repair, mitochondrial dysfunction, and cellular senescence. These disruptions collectively manifest as a multisystem disorder characterized by failure to thrive, accelerated atherosclerosis, and severe complications such as myocardial infarction, heart failure, stroke, and risks associated with head trauma or surgical interventions. Farnesyltransferase inhibitors (FTIs) have shown potential in mitigating disease phenotypes in preclinical models, with lonafarnib achieving FDA approval in 2020 as the first-and currently only-drug for progeria treatment. This review focuses on the clinical trial outcomes of small-molecule therapeutics for progeria, with particular emphasis on emerging small molecules from recent research. These novel compounds, with their unique mechanisms of action, hold promise not only for improving disease management but potentially offering a cure for this devastating condition.