ASO-mediated splicing correction for LMNA c.1608+5G>A in Hutchinson-Gilford progeria syndrome

LMNA c.1608+5G>A is a deep intronic splice-site variant that disrupts the consensus 5' donor site of intron 11, likely activating a cryptic splice site and generating an in-frame insertion that mimics progerin-like mRNA processing. Antisense oligonucleotide (ASO) therapy targeting the aberrant splice junction or the cryptic exon inclusion region represents the most mechanistically precise intervention. Concurrent farnesyltransferase inhibitor (lonafarnib) treatment addresses progerin protein toxicity orthogonally and should be considered as a combination backbone while ASO development matures.

The canonical HGPS mutation c.1824C>T (p.Gly608Gly) creates a cryptic splice site generating progerin with 50-aa deletion in exon 11—establishing the mechanistic precedent that exon 11 splicing is highly sensitive to sequence perturbations. Scaffidi & Misteli (Nat Med 2005, PMID:16116426) demonstrated that ASOs blocking the cryptic splice site in the canonical HGPS mutation restored normal lamin A splicing in patient fibroblasts. Lonafarnib (Zokinvy) received FDA approval in 2020 (PMID:33170951) based on 2.5-month median survival extension in HGPS, validating the progerin farnesylation pathway as a druggable target. For c.1608+5G>A, SpliceAI prediction (delta score >0.5 threshold) and ViennaRNA secondary structure modeling of the intron 11 region are recommended to define the cryptic exon boundary and design the ASO targeting window with optimal mismatch-free complementarity.

The cryptic splice product generated by c.1608+5G>A has not been experimentally characterized in patient-derived fibroblasts or iPSCs—establishing the precise aberrant mRNA isoform is prerequisite to ASO design. If the variant activates a novel cryptic donor rather than modifying exon 11 length, the resulting protein may differ structurally from canonical progerin, altering therapeutic strategy. ASO delivery to cardiovascular tissue (smooth muscle, endothelium) remains challenging—systemic 2'-MOE phosphorothioate ASOs achieve good liver and kidney distribution but poor vascular wall penetration, which is critical given that HGPS mortality is driven by accelerated atherosclerosis. Long-term ASO dosing in pediatric patients requires careful safety monitoring for thrombocytopenia and complement activation, known class effects.