RNAi modulation of placental sFLT1 for the treatment of preeclampsia
AuthorsTuranov, Anton A.
Hassler, Matthew R.
Alterman, Julia F.
Coles, Andrew H.
Haraszti, Reka A.
Godinho, Bruno M. D. C.
Karumanchi, S. Ananth
Moore, Melissa J.
KeywordsBiochemistry, Biophysics, and Structural Biology
Female Urogenital Diseases and Pregnancy Complications
Genetics and Genomics
Maternal and Child Health
Nucleic Acids, Nucleotides, and Nucleosides
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AbstractPreeclampsia is a placentally induced hypertensive disorder of pregnancy that is associated with substantial morbidity and mortality to mothers and fetuses. Clinical manifestations of preterm preeclampsia result from excess circulating soluble vascular endothelial growth factor receptor FLT1 (sFLT1 or sVEGFR1) of placental origin. Here we identify short interfering RNAs (siRNAs) that selectively silence the three sFLT1 mRNA isoforms primarily responsible for placental overexpression of sFLT1 without reducing levels of full-length FLT1 mRNA. Full chemical stabilization in the context of hydrophobic modifications enabled productive siRNA accumulation in the placenta (up to 7% of injected dose) and reduced circulating sFLT1 in pregnant mice (up to 50%). In a baboon preeclampsia model, a single dose of siRNAs suppressed sFLT1 overexpression and clinical signs of preeclampsia. Our results demonstrate RNAi-based extrahepatic modulation of gene expression with nonformulated siRNAs in nonhuman primates and establish a path toward a new treatment paradigm for patients with preterm preeclampsia.
Nat Biotechnol. 2018 Nov 19. pii: nbt.4297. doi: 10.1038/nbt.4297. [Epub ahead of print] Link to article on publisher's site
Permanent Link to this Itemhttp://hdl.handle.net/20.500.14038/29382
Full author list omitted for brevity. For the full list of authors, see article.