Abnormally high levels of soluble FLT1 (sFLT1; also known as sVEGFR1) have a key role in the pathogenesis of pre-eclampsia. Now, Ananth Karumanchi and colleagues have developed an RNA interference (RNAi) approach to modulate sFLT1 expression that ameliorates pre-eclampsia in animal models.

“Our desire was to develop a simple and cost-effective pre-eclampsia therapeutic using RNAi to limit excess placental expression of sFLT1 proteins,” explains Karumanchi. “Placental sFLT1 expression is dominated by three truncated mRNA isoforms that are generated by polyadenylation within Flt1 introns 13 and 14. Targeting these intronic regions using RNAi enables silencing of the abnormally expressed truncated mRNA variants that encode sFLT1 proteins without interfering with the expression of full-length FLT1.”

Using a systematic screening process, the researchers identified two hydrophobically modified asymmetric small interfering RNAs (hsiRNAs) that selectively silenced sFLT1 mRNAs in cultured human cytotrophoblasts. Following intravenous administration, chemically stabilized, cholesterol-conjugated versions of these hsiRNAs accumulated in the placentas of pregnant mice and reduced circulating sFLT1 levels with no adverse effects on the animals or their pups.

Similarly, injection of the hsiRNAs substantially reduced the levels of circulating sFLT1 proteins in a baboon model of pre-eclampsia. The treated animals showed reductions in blood pressure and proteinuria but no significant difference in birth weights compared with controls.

“I believe that our study demonstrates that we can target the placenta safely,” comments Karumanchi. “Therefore, our approach opens the door for a variety of other placental targets for pre-eclampsia and other related disorders.”