Selection of specific and efficient siRNAs in new cellular model for Hutchinson-Gilford progeria syndrome therapy.

Hutchinson-Gilford progeria syndrome is a fatal genetic disorder caused by a point mutation in the gene encoding the nuclear envelope protein lamin A/C. The most frequent mutation leads to the synthesis of a shorter version of lamin A named progerin, which accumulates under the nuclear membrane, leading to nuclear lamina disorganization and affecting gene expression and signaling. In our study, we designed a set of small interfering RNA (siRNA) sequences for the selective and efficient downregulation of progerin level and tested them in our new progeria HeLa cellular model and patients' fibroblasts. We showed efficient downregulation of progerin level without affecting endogenous lamin A or lamin C levels. Additionally, we observed an additive effect of the combination of our siRNAs with lonafarnib-the sole drug approved by the Food and Drug Administration for progeria syndrome therapy. The selected siRNAs also worked efficiently in all three tested patient fibroblast lines, even after extended post-transfection incubation with low siRNA doses. Therefore, we believe that the development of genetic drugs may be a promising therapeutic tool for Hutchinson-Gilford progeria syndrome.