Currently, the only available treatment for pregnancies with preeclampsia (PE) is delivery of the fetus, regardless of gestational age. A research collaboration from the RNA Therapeutics Institute at the University of Massachusetts Medical School (UMMS) and Western Sydney University is hoping to give those women another option, to avoid the potentially devastating results of early delivery.
In a study published today in Nature Biotechnology, entitled “RNAi modulation of placental sFLT1 for the treatment of preeclampsia,” the researchers show successful blockage of sFLT1 synthesis in the placenta using small interfering RNA (siRNA) delivered intravenously or subcutaneously. The treatment reduced circulating levels of sFLT1 in pregnant mice and in a baboon model of preeclampsia. In contrast to previous work, the approach suppresses placental sFLT1 with only a single injection.
Melissa Moore, Ph.D., professor at the RNA Therapeutics Institute at UMMS, and senior author on the paper, tells GEN that this research has “identified a lead compound for a treatment that could reduce the maternal signs of PE for a long enough time to make a difference.”
Excess circulating soluble vascular endothelial growth factor receptor sFLT1, which is produced by the placenta and secreted into the blood, was identified as the cause of the symptoms associated with preeclampsia 15 years ago. sFLT1 proteins are Tyrosine-protein kinases that act as a cell-surface receptors for VEGFA, VEGFB, and PGF, and play an essential role in the development of embryonic vasculature, the regulation of angiogenesis, cell survival, cell migration, etc. Lowering the activity of sFLT1 has been a promising therapeutic target for PE; however previous attempts at doing so through small molecules and antibodies have failed.
In this study, the researchers identified siRNAs that selectively silence the three sFLT1 mRNA isoforms primarily responsible for placental overexpression of sFLT1 without reducing levels of full-length FLT1 mRNA. Hydrophobic modification of the siRNAs (hsiRNA) allowed for siRNA accumulation in the placenta and reduced circulating sFLT1 in pregnant mice.
Testing the system in a preeclampsia model of nonhuman primates was made possible through collaboration with Annemarie Hennessy, MBBS, Ph.D., dean of the school of medicine at Western Sydney University, Australia, who has been using this model for over 20 years. As Anastasia Khvorova, Ph.D., professor at the RNA Therapeutics Institute at the UMMS tells GEN, “Dr. Annemarie’s lab is the only one in the world running PE nonhuman primate models, which was critical for our collaborative paper.” In the baboon preeclampsia model, a single dose of siRNAs suppressed sFLT1 overexpression and clinical signs of preeclampsia. The baboon model “approximates many features of the human disease.” Says Ananth Karumanchi, M.D., professor of medicine at the Beth Israel Deaconess Medical Center and Harvard Medical School. He notes, “In contrast to rodents, duration of pregnancy and placentation in baboons is similar to humans. However, this model does not develop all of the features of severe disease. Nevertheless, it is useful to evaluate proof-of-concept studies prior to initiating human studies.”
The formation of this collaboration is a story of both personal motivation and serendipity. Fifteen years ago, as Dr. Moore was being prepped for an emergency Cesarean section due to her PE, the physician assigned to her case, Dr. Karumanchi, asked permission to use the placenta for research, sparking a conversation about the current biological underpinnings of PE. When Dr. Karumanchi shared his most recent publication on the topic, a seminal paper on the role of sFLT1 as the causative agent of the symptoms of PE entitled “Excess placental soluble fms-like tyrosine kinase 1 (sFLT1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia,” Dr. Moore’s interest was piqued. Her own work in RNA processing led to a natural marriage of interests and the two started a formal collaboration in 2011.
When Dr. Khvorova, an expert in developing new siRNA chemistries, joined UMMS in 2012, the team gained the expertise they needed to enable the best possible strategies to target the placenta, supporting delivery and sustained silencing activity. The full chemical stabilization was achieved by all sugars being modified using an alternating 2’-fluoro and 2’-O-methyl modification pattern, all 5’- and 3’- terminal linkages being phosphorothioate-modified and labeling with Cy3 fluorescent dye. Dr. Karumanchi notes that he was “blown away by the elegance of the chemistry.”
Dr. Karumanchi states that, “we have learned more about the disease biology during last 10–15 years in the 21st century than the previous 100 years in the 20th century. I believe we now have several validated targets for testing novel therapies and I remain very optimistic that during the next decade, we will finally be able to offer novel treatments based on our understanding of the underlying mechanism.”
He realistically adds that they are “at least 3–5 years away from testing this in humans” and that the “timeline for testing in humans will depend on securing adequate funding to move this project along.” Dr. Moore agrees, saying, “We need more funding” and that “all of this work was done in academic labs. But, the next steps, the push to get this into the clinic, will require a lot more money.” She adds that pregnancy-related topics always carry a fear of adverse events and, to that end, caution is appropriate. However, she notes that “with all of the money that goes into drug development, pregnancy-related conditions are simply not being tackled enough” and she hopes that research like this will begin to turn that in a different direction.
