Fig. 7: ISR pathway biomarkers are reduced in ex vivo stimulated PBMCs after multiple dose administration of DNL343 in healthy and ALS participants.

a−d ATF4 protein (a) and CHAC1 gene (b) expression in ex vivo stimulated PBMCs from healthy participants. ATF4 protein (c) and CHAC1 gene (d) expression in ex vivo stimulated PBMCs from ALS participants. PBMCs were freshly isolated from participants in each dose group shown at the times indicated and analyzed by either ECLIA (a, c) or multiplex qPCR (b, d). Values shown as median (IQR = interval from the first to the third quartile, shown as error bars) percent change from baseline. For MAD healthy participants ATF4 protein, n = 12, 6, 7, 7, 7, 6 participants for placebo, 45 mg, 100 mg, 145 mg, 200 mg and 260 mg groups respectively; CHAC1 gene, n = 11, 6, 7, 5, 7, 6 participants for placebo, 45 mg, 100 mg, 145 mg, 200 mg and 260 mg groups respectively. For ALS participants ATF4 protein, n = 6, 7, 6 participants for placebo, 100 mg, and 200 mg groups respectively; CHAC1 gene, n = 5, 7, 6 participants for placebo, 100 mg, 200 mg groups respectively through Day 28 for each dose group. e Heat map depicting relative change from baseline for a panel of ISR genes. Gene expression measured by multiplex qPCR in freshly isolated ex vivo stimulated PBMCs from ALS patients in each dose group. Values grouped based on median percent change from baseline and genes rank ordered based on percent change from baseline at Day 28 in the highest dose cohort (200 mg). f Percent change from baseline in CSF GDF-15 protein concentration at Day 28 in ALS participants, n = 9, 8, 8 participants for placebo, 100 mg, 200 mg groups respectively per group. Data are shown as box plot with individual percent change values overlayed. The middle line of the boxplot displays the median, the lower and upper limits of the box display the first and third quartiles, and the whiskers extend to the largest and smallest values. Source data are provided in Source Data file.