At 31 weeks of gestation, I was admitted to Beth Israel Hospital in Boston because my platelets kept dropping – I was developing HELLP syndrome. [HELLP stands for Hemolysis, ELevated liver enzymes, and Low Platelet count.] There I met Dr. Ananth Karumanchi, who had just published his seminal paper in the Journal of Clinical Investigation on the protein sFlt-1 and its role in preeclampsia. I continued to bump into Dr. Karumanchi over the following seven years, as our daughters attended the same pre- and elementary schools and took gymnastics together. Our daily lives kept throwing us together in unexpected ways. In 2010, we ended up at the same scientific conference. By then, I was a co-director of the RNA Therapeutics Institute at UMass Medical School, and so I was very interested in applying my knowledge of RNA to create therapeutics. Also at that time, the Bill and Melinda Gates Foundation had issued a request for proposals for their Grand Challenges grant program targeting infant and maternal health. Dr. Karumanchi and I applied for and received that funding to begin development of a siRNA therapeutic for preeclampsia. That was the beginning of another eight years of hard work by our two research groups in collaboration with other colleagues at UMass Med (particularly Dr. Anastasia Khvorova’s group) and in Sydney, Australia, to refine and test our drug candidate.

Can you explain what sFlt-1 is and how it plays a role in the development of preeclampsia?

sFlt-1 is a protein made by the placenta and secreted into the maternal bloodstream. It is normally made near the very end of pregnancy, but in preeclampsia it begins to be made much earlier. sFlt-1 is a so-called anti-angiogenic protein, meaning that it interferes with the formation and maintenance of blood vessels. It is believed that excess sFlt-1 levels in the maternal bloodstream damage the layer of cells known as the endothelium that line the mother’s blood vessels. This results in the hallmark symptoms of disease like dangerously high blood pressure and proteinuria, which is a sign of kidney damage. But because the placenta is the main source of sFlt-1 during pregnancy, once the placenta is delivered along with the baby, maternal symptoms usually improve within a few days.

What are RNA therapeutics, and why do you believe they hold potential for treating conditions like preeclampsia?

RNA therapeutics utilize our accumulated knowledge of how proteins are made by the body to either increase or decrease production of a particular protein. The molecular instructions for making proteins come in the form of messenger RNA, or mRNA, with the amount of protein produced being directly proportional to the amount of mRNA present. The molecules we designed, which ultimately became Comanche Biopharma’s investigational medicine, CBP-4888, are small interfering RNAs, or siRNAs. siRNAs can be thought of as highly specific molecular scissors – they cause the cleavage and destruction of just the mRNA to which they are targeted. The siRNAs in CBP-4888 were designed to target the mRNA instructions for making sFlt-1. Our hypothesis is that by decreasing the amount of sFlt-1 mRNA produced by the placenta, CBP-4888 may have the ability to decrease the level of sFlt-1 protein in maternal circulation.

You’ve described this project as your passion project. Could you elaborate on why developing this therapeutic has become such a pivotal endeavor for you?

A shocking realization for me when I was diagnosed with preeclampsia was how little the treatment of this devastating disorder had changed over the last century, even as treatment for non-pregnancy-related conditions saw huge advances. Like numerous disorders experienced solely by people with uteri, preeclampsia had been largely neglected by the medical establishment. As a woman this was infuriating to me. But one of the wonderful things about being a scientist is that we often have the knowledge and expertise to do something about afflictions that affect us personally. 

Once I realized there could be a potential solution to this problem using siRNA, I felt compelled to work on it. With the know-how to create molecules based on deep molecular understanding of how we can modulate the body’s ability to synthesize specific proteins, there was simply no excuse for us not to try. My preeclampsia baby is now 20 years old. My hope is that by the time she and her sister decide to have children (should they do so), they will not need worry about whether their lives and those of their unborn children could be put in danger by this disease.

The views and opinions expressed by members of Comanche Biopharma’s Patient Advisory Board in the ‘Preeclampsia Champions of Change Q&A Series’ may not necessarily reflect the views and opinions of the company.