Future Food Sandpit on Early Life Nutritional Opportunities leads to successful ZonMw project

Overview of the postulated intranasal routes of milk EV delivery to the brain, neural target cells, and EV cargo that could promote neural cells to protect the brain from EoP in preterm infants.

Human milk serves as our first functional nourishment, providing a vital foundation for life's journey. Human milk contains a diverse array of nutrients and bioactive compounds that actively contribute to healthy brain development. Particularly in preterm-born infants, human milk plays a significant role in the protection against the life-long neurodevelopmental impairments that originate from preterm brain injury. At present, only supportive care is available and new treatments that inhibit inflammatory damage or boost regeneration of the preterm brain are urgently needed. Importantly, mother’s own milk feeding in preterm infants is beneficial for preterm brain growth and connectivity. However, the mechanisms underlying the beneficial effects of human milk on the preterm brain remain inadequately elucidated.

Human milk is notably abundant in extracellular vesicles (EVs), small vesicles released by cells for intercellular communication. Recently, we and others demonstrated strong anti-inflammatory and immune modulatory properties of human milk EVs. Interestingly, EVs can cross biological borders and intranasal application of stem cell EVs is an effective route to target the brain, where they can have anti-inflammatory and neuroregenerative effects on various brain cells. Targeting of milk EVs to the brain has never been investigated and the therapeutic effects of milk EVs on brain cells remain unknown.

In the wake of the 2021 Future Food Utrecht Sandpit event themed "Early life nutritional opportunities for a resilient life" and the Conversation Series "Mother's little secrets in milk", a multidisciplinary team of scientist secured funding from the ZonMw Open Competition to investigate the therapeutic effects of milk EVs on the injured preterm brain. In June 2023, neonatologist Prof. Manon Benders and translational neuroscientist Dr. Caroline de Theije affiliated with UMC Utrecht together with cell biologist Prof. Marca Wauben from the Utrecht University, Faculty of Veterinary Medicine embarked on this multidisciplinary research project titled "Breast milk Extracellular Vesicles for Baby Brains (EV4BB)". By taking a bench-to-bedside approach, EV4BB aims to decipher the anti-inflammatory and regenerative mechanism of action of milk EVs on various brain cell types and to connect their modulatory activities  to crucial milk EV cargo components identified by multi-omics approaches. Additionally, targeting of milk EVs to the brain following intranasal application and its successive therapeutic effects will be determined in an in vivo model for preterm brain injury. Lastly, EV4BB aims to determine the feasibility and safety of intranasal administration of milk EVs in preterm babies to target the injured brain. The goal of this project is to deliver a protocol for a first-in-human clinical efficacy trial to determine whether intranasal breast milk therapy can reduce brain injuries in preterm infants.