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.

Grant Number: 1R21HD117430-01A1
NIH Institute/Center: NIH
Principal Investigator: Jonah Chan