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Personalized Therapy Against Preeclampsia by Replenishing Placental Protein 13 (PP13) Targeted to Patients With
Hamutal Meiri1, George Osol2, Irene Cetin3,4
1Hy Laboratories, Rehovot, and TeleMarpe, Tel Aviv, Israel.
Insights
Preeclampsia (PE) risk can be predicted by low placental protein 13 (PP13) levels. Targeted PP13 therapy shows promise for preventing and treating PE, improving maternal and newborn outcomes.
Area of Science:
- Obstetrics and Gynecology
- Maternal-Fetal Medicine
- Biochemistry
Background:
- Hypertensive disorders, including preeclampsia (PE), affect millions of pregnant women globally, leading to severe maternal and newborn complications.
- Current anti-hypertensive drugs are ineffective for PE, and while aspirin helps prevent preterm PE, it doesn't cure most cases.
- Biomarkers are crucial for predicting PE development, with placental protein 13 (PP13) emerging as a key indicator.
Purpose of the Study:
- To review the role of placental protein 13 (PP13) in preeclampsia (PE) development and progression.
- To explore the potential of targeted PP13 therapy for PE prevention and treatment.
- To discuss the implications of PP13 genetic variants and their association with PE risk.
Main Methods:
- Review of published literature on placental protein 13 (PP13) and its association with preeclampsia (PE).
- Analysis of PP13 genetic variants, including promoter polymorphisms and deletions, and their impact on PP13 expression.
- Examination of preclinical data on PP13 replenishment in pregnant rodent models.
Main Results:
- Reduced PP13 levels, associated with specific PP13 genetic variants (e.g., -98 "A/A" genotype, DelT221), predict a higher risk of developing PE.
- PP13 replenishment in rodent models demonstrated reversible hypotension, uterine vasodilation, and improved fetal growth.
- Wild-type PP13 was shown to induce leukocyte apoptosis, crucial for maternal immune tolerance during pregnancy.
Conclusions:
- PP13 serves as a valuable predictive biomarker for preeclampsia (PE).
- Targeted PP13 therapy presents a promising novel strategy for PE prevention and treatment.
- Further animal studies are warranted to validate PP13 therapy before human clinical trials, aiming for integrated prediction and prevention strategies.
Abstract:
Hypertensive disorders affect about one third of all people aged 20 and above, and are treated with anti-hypertensive drugs. Preeclampsia (PE) is one form of such disorders that only develops during pregnancy. It affects ten million pregnant women globally and additionally causes fetal loss and major newborn disabilities. The syndrome's origin is multifactorial, and anti-hypertensive drugs are ineffective in treating it. Biomarkers are helpful for predict its development. Generic drugs, such as low dose aspirin, were proven effective in preventing preterm PE. However, it does not cure the majority of cases and many studies are underway for fighting PE with extended use of additional generic drugs, or through new drug development programs. This review focuses on placental protein 13 (PP13). This protein is only expressed in the placenta. Impaired PP13 DNA structure and/or its reduced mRNA expression leads to lower blood PP13 level that predict a higher risk of developing PE. Two polymorphic PP13 variants have been identified: (1) The promoter PP13 variant with an "A/A" genotype in the -98 position (versus "A/C" or "C/C"). Having the "A/A" genotype is coupled to lower PP13 expression, mainly during placental syncytiotrophoblast differentiation and, if associated with obesity and history of previous preeclampsia, it accurately predicts higher risk for developing the disorder. (2) A thymidine deletion at position 221 causes a frame shift in the open reading frame, and the formation of an early stop codon resulting in the formation of DelT221, a truncated variant of PP13. In pregnant rodents, both short- and long- term replenishment of PP13 causes reversible hypotension and vasodilation of uterine vessels. Long-term exposure is also accompanied by the development of larger placentas and newborns. Also, only w/t PP13 is capable of inducing leukocyte apoptosis, providing maternal immune tolerance to pregnancy. Based on published data, we propose a targeted PP13 therapy to fight PE, and consider the design and conduct of animal studies to explore this hypothesis. Accordingly, a new targeted therapy can be implemented in humans combining prediction and prevention.