Awarded Grants

Eric Reiter of the Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE) in France will engineer nanobody-based biologicals to block ovulation as a practical, non-hormonal contraceptive with fewer side effects. Blocking the molecular regulators of ovulation is an attractive contraceptive mechanism. However, it can also affect steroid hormone production, which causes undesirable side-effects. Nanobodies are antigen-binding domains of antibodies that can very selectively modulate signal transduction pathways. They will identify candidate nanobodies that may selectively block ovulation using a phage display approach and functional screens. Specifically, this work will focus on identifying nanobodies that are biased ligands, triggering receptors selectively to yield only the desired downstream responses. These candidates will be engineered to produce long-lasting biologicals that will then be administered to mice and ewes to evaluate their ability to block ovulation as a proof-of-principle.

Leo Han of Oregon Health and Science University in the U.S. and colleagues at the University of North Carolina and the Marsico Lung Institute will build a hydration-based drug discovery platform for the cervix to screen drug libraries for long-lasting non-hormonal contraceptives that alter mucus hydration. Contraceptives that thicken cervical mucus to block the movement of sperm and thereby inhibit fertility would be well tolerated and may also protect against pathogens. Identifying nonhormonal drugs that work in this way, however, is difficult because of the lack of relevant cell culture systems for high-throughput testing. They have previously conditionally reprogrammed endocervical cells to grow in culture while retaining relevant physiological characteristics such as hormonal regulation and mucus production. They will adapt this method for high-throughput screens by incorporating particle-based tracking microrheology to quantify hydration of the mucus layer produced by the cells that can then be used to screen drug libraries.

Stephanie Seminara of Massachusetts General Hospital in the U.S. will perform large-scale, human genetic studies to identify gene variants that influence fertility for developing novel non-hormonal contraceptives. Globally, many women do not use contraceptives for reasons including negative side effects of hormonal methods, leading to poor method acceptability. This leads to 88 million unintended pregnancies per year globally. To identify drug targets for developing more acceptable contraceptives, they will analyze whole exome sequences and phenotypes from three existing patient populations with rare forms of infertility, such as primary ovarian insufficiency, and one new cohort with unexplained infertility. This will reveal both single nucleotide and structural variants underlying infertility, and subsequently the associated molecular pathways. They will also perform a large-scale genome-wide association study using over 1.8 million samples from multi-ethnic population biobanks to identify common variants associated with reproductive traits, which could also uncover novel genes involved in infertility.

Viviana Gradinaru of the California Institute of Technology in the U.S. will perform imaging-based, high-throughput screens using adeno-associated virus (AAV) delivery vectors to rapidly identify ovary-specific macromolecules that are essential for fertility and could be used to develop non-hormonal contraceptives. They will compile a comprehensive list of candidate ovary-specific macromolecules, including RNAs and micropeptides, by applying machine learning algorithms and structural analyses to existing datasets and also perform Riboseq on mouse and human ovarian tissues to identify all the proteins being translated. They will then test these candidates by developing an oocyte and follicle cell-based loss-of-function screening platform using AAV to safely, efficiently, and specifically deliver the macromolecule-targeting constructs to the cells. The most promising AAV-based candidates will then be tested directly in mouse follicle cultures and then in vivo to identify those that are critical for female fertility and have reversible effects.

Jeffrey Lee of the University of Toronto in Canada will engineer single-domain camelid antibodies (nanobodies) to block the interaction between two proteins exclusive to the sperm and egg that mediate their fusion and thereby fertilization, as affordable, non-hormonal contraceptives with fewer side effects. Nanobodies are exquisitely specific binding proteins that make attractive therapeutics because of their additional simplicity, stability, and smaller size compared to antibodies, also lowering the cost of their production. They hypothesize that their small size is well adapted to reach the site of sperm-egg binding and block this interaction. To generate specific nanobodies they will immunize alpacas or llamas with the purified sperm and egg proteins and use phage display and ELISA to isolate antigen-specific nanobodies. These will then be tested for their ability to block sperm-egg fusion using biophysical assays, mating, and IVF models.

Tanya Doherty of the South African Medical Research Council will assess different contracting models for the National Health Insurance, which has been charged with providing universal health services purchased from both the public and private sectors across South Africa, to ensure that cesarean sections are only performed when appropriate and safe. Key challenges are to ensure that rural and over-loaded regional hospitals are able to meet service demands for obstetric care and that inappropriate care practices of the private sector, particularly the high cesarean section rate, are not applied to the entire population. They will perform case studies at four rural and urban district hospitals to evaluate different pricing and remuneration models, such as a global fee irrespective of mode of child delivery and contracting private practitioners for rural areas, and document their effects on the rates and safety of cesarean sections, and overall costs.

Darryl Russell of the University of Adelaide in Australia will use genomics approaches to identify the molecular pathways that control ovulation for developing more non-hormonal contraceptives with fewer side effects. The classical progestin-based contraceptive pill disrupts natural hormone cycles; requires long-term, regular use; and causes a range of harmful side-effects. An alternative approach is an acute treatment that directly blocks ovulation – the release of the oocyte from the ovary. This research team earlier discovered unique and specialized roles for the progesterone receptor (PGR) in regulating ovulation in a mouse model. They will further characterize these specialized molecular mechanisms upstream and downstream of PGR induction in granulosa cells, which associate with the oocyte, with a focus on chromatin and transcription factors to identify unique drug targets that could be used to develop a contraceptive with fewer side effects.

Joshua Vogel of the Burnet Institute in Australia will generate evidence to support adoption of the new WHO Labor Care Guide to reduce the rate of cesarean sections and enhance the quality of care during childbirth by developing an implementation strategy for hospitals in India. In many low-middle income settings, women giving birth in busy hospitals are often alone, undermedicated, and inappropriately monitored, which increases the rates of cesarean sections. The WHO Labor Care Guide is a decision support tool for health workers to more effectively monitor labor progress and provide appropriate medical and supportive care. However, it has not been widely adopted. They will hold a workshop with providers, hospital administrators, and women's groups to develop and refine their implementation strategy. They will then conduct a cluster-randomized pilot trial in four maternity hospitals in India to test their strategy and evaluate its effect on the rate of cesarean sections and women's childbirth experiences.

Jody Lori of the University of Michigan in the U.S. will implement a WhatsApp platform for medical staff and community health workers in rural areas in Liberia to communicate with staff at larger hospitals to accelerate the referral and treatment of obstetric emergencies. Liberia has one of the highest maternal mortality rates in the world. Many of the leading medical causes of death, including obstructed labor, are preventable if the women were more quickly referred to higher level care centers where life-saving procedures like cesarean sections can be safely performed. They will test their approach at one referral hospital and 20 rural clinics by training community health workers to better identify obstetric emergencies and refer them on using the WhatsApp platform. At the referral hospital, they will implement an additional triage system to decrease the decision-to-delivery time for women requiring cesarean section, as well as ensuring the women are aware of and involved in the medical decisions.

Thomas Weiser of the Lifebox Foundation in the U.S. will implement their surgical infection prevention program, Clean Cut, in ten maternity hospitals in Ethiopia to reduce infections and other complications of C-sections, which account for around 15% of maternal deaths. To improve the safety of surgery, they developed Clean Cut, which uses training and improved management practices to promote compliance with six key safety standards including sterility of instruments and surgical sites, gowns and gloves, and appropriate use of antibiotics. They will adapt their program to C-sections and perform a stepped-wedge study at 10 hospitals over 24 months involving recruiting and training a dedicated improvement team and developing tailored process plans to implement the program. They will evaluate its effect on compliance with the safety standards and on patient outcomes. Note: This grant is funded by the UBS Optimus Foundation.