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Preclinical characterization of DUOC-01, a candidate cell therapy product derived from human banked umbilical cord blood intended for use in treatment of demyelinating diseases

      Allogeneic umbilical cord blood [CB] transplantation can slow or reverse progression of central nervous system demyelination in inherited metabolic diseases. Clinical observations suggest that several months are required after transplant for donor derived cells in the brain to provide benefit. We are developing DUOC-01 as a bridging cell product administered intrathecally to patients early post-transplant to provide therapeutic effects prior to CNS engraftment by cells from the CB transplant. DUOC-01 is manufactured under cGMP conditions from the 20% compartment of the same CB unit used for systemic transplantation by a modification of a previously described method. We performed preclinical characterization of DUOC-01. Time lapse imaging showed that the cultures evolve into attached, motile, highly active cell populations resembling macrophages. The cells express characteristic myeloid macrophage markers including CD45, CD11b, and Iba1. Cells had activities of 11 disease-relevant lysosomal enzymes similar to wild type blood leucocytes. All DUOC-01 batches secreted IL-6 and IL-10. Some secreted TGF-β, IL-1β, INF-γ, TNF-α or very low amounts of IL-12 or IL-2. IL-4, IL-5 and IL-13 were not detected. Peripheral blood mononuclear cells [MNC] proliferated and released cytokines in response to DUOC-01. CB MNC did not respond to DUOC-01 made from the same unit, and DUOC-01 did not proliferate in response to mismatched MNC. Following intrathecal injection DUOC-01 cells were targeted to and persisted in brains and spinal cords of newborn NOD/SCID-IL2Rγnull mice for up to 56 days. Brains of NOD-SCID mice injected intrathecally or intracerebrally with DUOC-01 showed no tumors, ectopic tissue growth, or gross clinical abnormalities during 56 days of observation. DUOC-01 accelerated remyelination in NOD/SCID-IL2Rγnull mouse brains following curpizone feeding. Thus, preclinical studies suggest that DUOC-01 has promise as a candidate cell therapy for demyelinating diseases.
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