a, Schematic drawing of lamin A, lamin C and progerin mRNA produced through alternative splicing of LMNA. Target A, ASOs targeted to progerin alternative 5′ splice site; Target B, LMNA intron 11–exon 12 splice junction; Target C, progerin-specific E11–E12 splice junction; E11*, exon 11 lacking the terminal 150 nts. Dashed arrow indicates alternative splicing leading to progerin mRNA. Nucleotide in red indicates the HGPS disease-causing point mutation; pA, polyadenylation signal. b, Schematic diagram of ASO libraries. ASOs with different chemistries and various lengths targeted to different targeting regions are indicated. Color code for progerin mRNA reduction: black 0–50%, blue 50–75%, green 75–95% green and red >50% increase. ASOs connected with dotted lines are targeted to progerin mRNA and E11*E12. cEt, 2′, 4′-constrained ethyl; MOE, 2′-O-methoxyethyl. For sequence information of all ASOs, see Supplementary Table 2. ss, splice site; UTR, untranslated region.