Abstract: FR-PO346
Long-Lasting RNAi Therapeutics Targeting Angiotensinogen Induces a Robust and Durable Antihypertensive Effect
Session Information
- Hypertension and CVD: Mechanisms - I
October 26, 2018 | Location: Exhibit Hall, San Diego Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Hypertension and CVD
- 1403 Hypertension and CVD: Mechanisms
Authors
- Uijl, Estrellita, Erasmus Medical Center, Rotterdam, Netherlands
- Mirabito Colafella, Katrina M., Monash University, Clayton, New South Wales, Australia
- Hoorn, Ewout J., Erasmus Medical Center, Rotterdam, Netherlands
- Kim, Jae B., Alnylam Pharmaceuticals, Cambridge, Massachusetts, United States
- Foster, Donald J., Alnylam Pharmaceuticals, Cambridge, Massachusetts, United States
- Danser, Alexander H., Erasmus Medical Center, Rotterdam, Netherlands
Background
All angiotensin stems from angiotensinogen (AGT). A single dose of small interfering ribonucleic acids (siRNA) targeting AGT may provide long-lasting blood pressure reductions, as it would abolish angiotensin generation. Here we assessed efficacy of AGT siRNA in spontaneously hypertensive rats (SHRs).
Methods
SHRs were treated for 4 weeks with vehicle, siRNA (10 mg/kg; s.c. every 2 weeks), valsartan (31 mg/kg/day; oral), captopril (100 mg/kg/day; oral), valsartan+siRNA, or captopril+valsartan (all groups n=8). Mean arterial pressure (MAP) was measured via radiotelemetry.
Results
Baseline MAP was 137±2 mmHg. ΔMAP was largest after valsartan+siRNA (-67±3 mmHg; P<0.01 vs. captopril+valsartan), followed by captopril+valsartan, captopril, siRNA and valsartan (-55±4, -24±2, -14±1, and -9±2 mmHg, respectively). Valsartan+siRNA reduced cardiac hypertrophy the most (P<0.05 vs. captopril+valsartan). No treatment affected glomerular filtration rate or albuminuria. After 4 weeks, siRNA lowered AGT by 98.6%, which increased to 99.9% in combination with valsartan. All treatments increased renin, the highest rise occurring after valsartan+siRNA. Yet, only valsartan+siRNA lowered angiotensin II. No treatment altered aldosterone. Plasma K+ tended to increase in all groups, significance being reached only in the valsartan+siRNA group. Both types of dual blockade attenuated normal growth from the second week of treatment onwards.
Conclusion
In conclusion, due to renin upregulation, circulating angiotensin II remained intact even with only 1.4% of AGT left, relative to pretreatment. Consequently, AGT siRNA caused a similar antihypertensive effect as valsartan and captopril. Importantly, when combining siRNA+valsartan, angiotensin II collapsed, and blood pressure decreased synergistically. Given the potential for a low dosing frequency, this novel treatment may address medication adherence problems in patients with resistant hypertension and further development is warranted.