Abstract 666: RNAi Therapeutics Targeting Human Angiotensinogen (hAGT) Ameliorate Preeclamptic Sequelae in an Established Transgenic Rodent Model for Preeclampsia

Preeclampsia, a disorder with the hallmark features of new-onset hypertension and proteinuria beginning after 20 weeks of gestation, affects 5% of pregnancies in industrialized nations. It is a major cause of fetal and maternal morbidity/mortality. Several studies have demonstrated that angiotensinogen is involved in the pathogenesis of the disease; however, treatment with ACE Inhibitor or AT1 Receptor blocker is contraindicated due to fetal toxicity. RNAi therapeutics are highly potent mediators of gene-specific silencing. We tested a human angiotensinogen (hAGT)-specifc siRNA, conjugated to triantennary GalNAc, for the ability to ameliorate symptoms of preeclampsia in an established rat model, without affecting the fetus. Transgenic rats expressing hAGT and human renin (hREN) were crossed to produce a model of preeclampsia (PE rat) in the dams. Beginning on day 3 of gestation, transgenic hAGT dams were dosed subcutaneously with 10 mg/kg siRNA every third day through gestation day 15. Mean blood pressure was continuously recorded by radiotelemetry and 24 hour urine samples were collected in metabolic cages at day 18 of gestation. Rats were euthanized at day 21 of gestation. Treatment with the GalNAc-conjugated siRNA reduced the spike in blood pressure seen on gestation day 13 and lasted through study termination (MAP on day 16 of gestation: 155.1 ± 1.4 mmHg untreated vs. 138.4 ± 1.8 mmHg treated). Proteinuria was ameliorated (21.7 ± 3.1 mg/d untreated vs. 2.7 ± 0.6 mg/d treated) and levels of agonistic autoantibodies against the angiotensin receptor AT1 were reduced below the limit of detection. Fetal and uteroplacental unit weights increased with RNAi therapy, demonstrating a reduction in intra-uterine growth restriction (brain to liver ratio (0.95 ± 0.04 untreated vs. 0.73 ± 0.02 treated). mRNA levels of hAGT were reduced to background levels in the liver, but were not affected in the placenta, which is of fetal origin. Our data show that an RNAi therapeutic targeting hAGT ameliorates the clinical sequelae of preeclampsia in a transgenic rat model and improves the outcome of the fetus.