Investigating the therapeutic potential of maternal breast milk components for preterm white matter injury

SUMMARY White matter injury (WMI) is the most common type of brain injury in premature infants and is associated with adverse neurological outcomes, including motor and cognitive disability and seizures. There are no effective treatments for preterm WMI. Translation of potential therapies from animal models to neonates has been slow

due to safety and regulatory concerns, while technical barriers to screening methods have limited the identification of additional candidate treatments. Oligodendrocytes (OLs) and their precursors (oligodendrocyte precursor cells, OPCs) comprise the major cell types implicated in preterm WMI, which involves an arrest of

differentiation of OPCs and a reduction in mature OLs and myelin formation. Thus, the OL lineage is an ideal target for treatment of preterm WMI. Here, we demonstrate the development of a therapeutic pipeline for preterm WMI in which pro-myelinating compounds are identified using a novel high-throughput screening

method, followed by in vitro and in vivo validation and testing. Using our fabricated micropillar arrays, we propose to screen naturally occurring nutritional compounds found in breast milk to identify/confirm/validate compounds and pathways that promote myelination. Based on extensive data of beneficial outcome

measures in breastfed infants, and preliminary data supporting pro-myelinating activity of a breast milk carbohydrate, N-acetylneuraminic acid (NANA), we propose that nutritional compounds in breast milk represent an untapped and promising approach for the development of therapeutics for WMI in premature infants. In this proposal we will: 1. Perform high-throughput screening of breast milk components

to identify pro-myelinating compounds, and 2. Test whether exogenous NANA promotes OPC differentiation and myelination in vitro and in vivo and determine the necessity and sufficiency of the lysosomal transporter sialin for this effect. Through the experiments proposed here, we are poised to make key insights into cellular

mechanisms regulating myelination that may lead to new treatments and molecular targets for preterm WMI, a critical global health problem that affects over 500,000 infants per year worldwide.