Fig. 6: Activity of a human PCSK9 EE in PCHs in vitro and cynomolgus monkeys in vivo.

a, In silico alignment of CpGs (the molecular target of the EE) between human and cynomolgus monkey around the PCSK9 TSS. Matched and unmatched CpGs are labeled in blue and yellow, respectively (84 out of 112 CpGs are matched). Note that the cynomolgus PCSK9 gene is located on the negative strand; hence, CpGs in the reverse complement (rev-comp) sequence are shown. b, Activity and potency of LNP formulation using the EE PCSK9-EE-V2 in cultured PHHs and PCHs were assessed by measuring secreted PCSK9 protein in the supernatant. IC₅₀ values are indicated. Results are shown as mean ± s.d. (n = 4 replicates per group). c, Dose–response of a single infusion of an LNP formulation with PCSK9-EE-V2 on circulating PCSK9 protein levels (left) and LDL-C (right) in cynomolgus macaques (n = 3 per group). Vehicle-treated animals received a single infusion of saline solution (n = 4). Results are shown as mean ± s.d. Plasma samples were obtained from two of the vehicle-treated animals at days 84 and 98. These data were averaged and plotted at day 91 to better visualize the group mean. d, Effect of a single administration of PCSK9-EE-V2 on CpG methylation levels in liver biopsy samples at 24 d after treatment. CpG location (first row) and the methylation percentage (0–100%) of each CpG dinucleotide at the cynomolgus PCSK9 locus for individual animals are shown. Note that liver biopsies were obtained for only two of the vehicle-treated animals shown in c. e, Pearson’s correlation (r) comparing average cynomolgus PCSK9 (cPCSK9) TSS methylation levels (day 24) versus cynomolgus PCSK9 protein levels (day 21) for individual animals shown in c and d. Two-sided P value is shown. Cyno, cynomolgus; IC₅₀, half-maximal inhibitory concentration.