RNA-Seq analysis of liver and peripheral nervous tissues from cynos treated with GS-8873.

GS-8873, an HBV RNA transcript suppressor involving the TENT4A/B RNA stabilization complex was evaluated in 13-week toxicity studies with 8 weeks of recovery. Cynomolgus monkeys were orally dosed by gavage at 0, 0.5, 1.5, 3 and 6 mg/kg/day. Neuroelectrophysiology testing was conducted at weeks 4 and 13 of dosing and at week 4 and 8 post-recovery. Adverse electrophysiology effects occurred by week 13 in both species with a dose response compared to controls. The mean latency percent change values were increased (>10%) by week 4 in the monkey cauda equina. Monkey 13 week latency values increased by 24% and 31% in the sural nerves and cauda equina respectively with reductions in NCV. The electrophysiology values did not return to vehicle control group levels after 8 weeks of recovery, although some reversal was evident. Monkey lumbar dorsal root ganglia samples from the 6 mg/kg/day dose group were evaluated by RNA-Seq and revealed 102 differentially expressed genes enriched for neuronal disease pathway associations compared to the controls. Overall design: 8 animals were used for oral dosing by gavage: 4 with 6 mg/kg/day and 4 with 0 mg/kg/day of HBV mRNA transcript inhibitor GS-8873 for 13-weeks. At the time of sacrifice, samples were collected from liver, spinal cord and dorsal root ganglia of each animal. Three spinal cord samples were obtained from each animal from cervical, thoracic and lumbar regions. Two Dorsal root ganglia samples were obtained from each animal from cervical and lumbar regions.