Systematic screening identifies therapeutic antisense oligonucleotides for Hutchinson-Gilford progeria syndrome.

Hutchinson-Gilford progeria syndrome (HGPS) is a rare, invariably fatal childhood premature aging disorder caused by a pre-messenger RNA (mRNA) splicing defect in the LMNA gene. We used combined in vitro screening and in vivo validation to systematically explore the effects of target sequence, backbone chemistry and mechanism of action to identify optimized antisense oligonucleotides (ASOs) for therapeutic use in HGPS. In a library of 198 ASOs, the most potent ASOs targeted the LMNA exon 12 junction and acted via non-RNase H-mediated mechanisms.

Identification of novel RNA isoforms of LMNA.

The nuclear lamina is a proteinaceous meshwork situated underneath the inner nuclear membrane and is composed of nuclear lamin proteins, which are type-V intermediate filaments. The LMNA gene gives rise to lamin A and lamin C through alternative splicing. Mutations in LMNA cause multiple diseases known as laminopathies, including Hutchinson-Gilford Progeria Syndrome (HGPS), a premature aging disorder caused by a point mutation that activates a cryptic 5' splice site in exon 11, resulting in a 150 bp deletion in the LMNA mRNA and the production of the dominant lamin A isoform progerin.