Abstract 28: Cord Blood Derived Macrophages Promote the Differentiation of Oligodendrocyte Precursor Cells

Introduction Krabbe Disease (KD) is a rare neurodegenerative disorder caused by a mutation in the gene encoding galactocerebrosidase (GALC). GALC deficiency leads to accumulation of the toxic metabolite psychosine in myelin-forming oligodendrocytes causing severe demyelination. Presymptomatic hematopoietic stem cell transplants can slow the progression of disease, but ultimately there is no cure. We previously demonstrated that DUOC-01, a first-generation macrophage cell-therapy manufactured from banked human umbilical cord blood cells, which when injected into the corpus callosum, enhanced remyelination in immunocompromised mice treated with the demyelinating agent, cuprizone. Further, DUOC-01 could promote the maturation of oligodendrocyte precursor cells (OPCs) into mature oligodendrocytes via remyelinating factors (Remy-Macs). Objectives In this study, we set out to test if DUOC-01 and their secreted Remy-Macs could rescue oligodendrocyte deficits and improve survival in GALC deficient mice. Methods First, we generated primary OPC cultures from GALC deficient mice and measured OPC maturation by immunohistochemistry and qRT-PCR of myelin basic protein (MBP). To test if DUOC-01 impacted OPCs via secreted factors, we incorporated the use of transwell assays. To test if DUOC-01 or Remy-Macs could promote remyelination in vivo, we injected DUOC-01 or used Alzet osmotic pumps to deliver therapies into the cerebrospinal fluid (CSF). Results We first tested the effects of DUOC-01 and Remy-Macs on primary OPC cultures isolated from neonatal control of GALC deficient mice. We observed comparable oligosphere growth in cultures derived from GALC deficient mice and their wild-type litter mates, indicating a normal function for twitcher OPC proliferation. However, OPC differentiation was compromised in GALC deficient mice, demonstrated by decreased MBP expression. DUOC-01 and Remy-Macs increased the production of MBP at both mRNA and protein levels. Additionally, infusion of Remy-Macs into the CSF of GALC deficient mice improved survival. Discussion Our data demonstrated that DUOC-01 or Remy-Macs promoted the differentiation of OPCs isolated from GALC deficient mice. Further, infusing Remy-Macs into the CSF of GALC deficient mice extended life span. Our data suggest DUOC-01 or Remy-Macs have the potential to be further developed into a novel cell-therapy to treat Krabbe and other demyelinating diseases.