Up to 30% of low birth weight preterm infants manifest some form of periventricular white matter injury (PWMI) making it the most common form of brain injury affecting premature infants. PWMI is associated with significant morbidity, as affected individuals may have profound intellectual impairment and cerebral palsy. Highlighting the magnitude of PWMI, each year more than 400,000 infants are born prematurely in the United States. Of these infants, 150,000 are born at risk for PWMI, and about 25,000 children per year will develop PWMI. Thus, finding a prevention and treatment for PWMI is of major public health importance. Oligodendrocytes (OLs) are the myelinating cells of the central nervous system and play a critical role in white matter formation. It is believed that loss of Pre-oligodendrocytes (PreOLs), which are proliferative cells that develop into myelinating OLs, plays a major role in PWMI causation. Presently, there are few pharmacological approaches that specifically target PreOLs, resulting in increased proliferation of these cells and increased brain myelination. Medosome Biotec, LLC (MBT) and its research partners at the University of Florida believe a significant market exists to develop and commercialize a therapeutic treatment for white matter injury in premature infants and other brain myelination disorders. To address the shortcomings of current therapeutics, the team, led by Dr. Scott Rivkees (PI) at University of Florida, used high-throughput screening to identify compounds that to stimulate PreOL proliferation. These studies identified 4 compounds as having potential merit. In preliminary studies, we assessed myelination and toxicological properties of these compounds in brain slice and in vivo studies. These studies identified the compound K261- 0298 as the most potent stimulator of myelination. This compound was subsequently tested in short-term and long-term toxicology studies in neonatal mice and found to be non-toxic. This compound also stimulated myelination in neonatal mice. Building on our promising data, the proposed STTR fast-track application will first focus on testing this compound for efficacy in models of white matter injury in the Phase1 component. If protective, as anticipated, in the Phase 2 component, we will be to perform IND-enabling studies that will lead to an IND and clinical studies. To achieve these goals, our team will include Drs. Avery and McCardy, who direct the University of Florida Translational Drug Development Core; Charles River and ChemDiv Laboratories, which are CROs with extensive experience in the execution of pre-IND testing; and Pharmlex which has more than 10 years of experience in assisting a pharmaceutical companies in the United States and around the world to bring new therapeutics to the marketplace. This project presents an excellent opportunity to commercialize novel approaches for treating and preventing white matter injury in the tens of thousands of premature infants born and hospitalized each year. As such, we have the opportunity to develop new therapeutics for a huge unmet need.
PROJECT NARATIVE Loss of Pre-oligodendrocytes (PreOLs), which are proliferative cells that develop into myelinating OLs, play a major role in white matter injury causation. Presently, there are few pharmacological approaches that specifically target PreOLs, resulting in increased proliferation and differentiation of these cells and increased brain myelination. The goal of this work is to develop novel therapeutic agents for the treatment of white matter injury in premature infants and other disorders of myelination.
