Targeting Remyelination to Treat Preterm Brain Injury - Contact P.I.: Ostrem, B.E.L. PROJECT SUMMARY Preterm white matter injury (PWMI) is the most common type of brain injury in premature infants and is associated with adverse neurological outcomes, including cerebral palsy, cognitive and learning disabilities, and seizures. PWMI is caused by a differentiation arrest in the oligodendrocyte (OL) lineage, and a failure of myelination. As there are no specific treatments, care is supportive and focused on rehabilitation. However, novel high-throughput screening methods have enabled the identification of remyelinating, or pro-myelinating, compounds that promote OL differentiation and myelination. We hypothesize based on overlapping mechanisms of remyelination and developmental myelination that remyelinating compounds are an untapped source of potential therapeutics for PWMI. Here, we demonstrate the development of a therapeutic pipeline for PWMI where remyelinating compounds are identified using a high-throughput in vitro screening platform, binary indicant for myelination using micropillar arrays (BIMA). Screen hits that meet key criteria suggestive of safety and feasibility in neonatal neurological applications are validated in vitro and tested in a murine chronic hypoxia model of PWMI. We further propose to complete a Phase I clinical trial of a promising remyelinating compound that has completed testing through our preclinical pipeline, clemastine, in neonates with PWMI. This oral antihistamine is approved in patients ages 3 and older for allergic indications and was recently shown to promote remyelination in adults with multiple sclerosis. Neonatal safety and pharmacokinetic (PK) data are needed prior to larger efficacy studies for PWMI. We will perform a Phase I/Ib dose expansion/dose escalation study to test the safety and PK of clemastine in preterm neonates with PWMI. We have worked closely with the FDA, expert collaborators, and parent advocates on an adaptive, PK-guided trial design that accounts for prior pitfalls in clinical trials for newborn brain disorders. We will enroll 20 neonates born at ≤32 weeks gestation, who have PWMI identified by neuroimaging. Neonates will be treated with clemastine for 14 days while undergoing close monitoring and blood sampling for PK measurements in the intensive care nursery. Blood and imaging biomarkers will be obtained at enrollment and 3 months after treatment and neurodevelopmental outcomes will be followed for 2.5 years on all participants. This trial will inform the dosing for and design of a randomized, placebo-controlled, Phase II trial of clemastine for PWMI. Overall, our high-throughput drug discovery platform combined with our neonatal feasibility and prioritization system is a new and promising approach to therapeutic development for PWMI. Our trial design will serve as a road map for similar future trials for conditions affecting the newborn brain. The application of remyelinating therapies to neonatal brain injury is conceptually innovative, and our preliminary data are highly supportive of the potential success of this approach. This work has the potential to fundamentally change the therapeutic landscape, and approach to drug development, for a devastating neonatal neurological problem with no current treatments.
