Hutchinson-Gilford progeria syndrome

The rare genetic autosomal dominant condition Hutchinson-Gilford progeria syndrome (HGPS) is characterized by a dramatic, rapid appearance of aging beginning in childhood. HGPS progression generates vascular disease, which generally leads to death during the teenage years. There is currently no treatment for this genetic disorder, although since the identification of the underlying genetic mutation, new targets and potential strategies have emerged. The large majority of HGPS cases carry a single nucleotide substitution within exon 11 of the LMNA gene and abnormal splicing results in production of a truncated prelamin A protein (progerin). Subsequent farnesylation of mutated prelamin A targets the protein to the nuclear envelope, resulting in nuclear deformations and blebbing. Recent studies have shown that blocking faraneylation of progerin via the use of farnesyl-transferase inhibitors can reduce nuclear blebbing and thus HGPS pathogenicity. Lentiviral administration of short hairpin RNA constructs to target and reduce progerin has also demonstrated efficacy in HGPS fibroblasts. Therefore, pharmacological targeting to correct cellular phenotypes associated with HGPS could be utilized in the future for therapeutics intervention.