Methods and compositions for modulation of migration of neurogenic cells
Inventors
Borlongan, Cesar V. • Case, Casey C.
Assignees
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Publication Number
US-10626389-B2
Publication Date
2020-04-21
Expiration Date
Abstract
Disclosed herein are methods for the treatment of traumatic brain injury by transplantation of cells descended from marrow adherent stem cells that express an exogenous Notch intracellular domain. The transplanted cells form a pathway along which endogenous neurogenic cells proliferate and migrate from the subventricular zone to the site of injury.
Core Innovation
The disclosure describes treating traumatic brain injury (TBI) by transplanting SB623 cells derived from marrow adherent stem cells (MSCs) engineered to express an exogenous Notch intracellular domain (NICD) lacking a full-length Notch protein. The engineered cells transiently form a biobridge pathway between the subventricular zone (SVZ) and the injured cortex, enabling endogenous neurogenic cell proliferation, differentiation, and migration from the SVZ to the injury site.
Therapeutic benefits are reported without long-term graft persistence, with the disclosure attributing effects to acute or modest graft survival and biobridge-associated upregulation of matrix metalloproteinase-9 (MMP-9) activity. The approach is presented in the context of inducing expression of MMP-9 in the central nervous system by introducing exogenous cells into the central nervous system.
In addition, the disclosed exogenous cells are generated by contacting a culture of marrow adherent stem cells (MSCs) with a polynucleotide encoding an NICD that does not encode a full-length Notch protein, selecting cells that comprise the polynucleotide, and further culturing the selected cells in adherent culture in the absence of selection.
Claims Coverage
The partial content includes one independent claim that covers a method for inducing matrix metalloproteinase-9 (MMP-9) expression in the central nervous system using exogenous cells derived from marrow adherent stem cells (MSCs) engineered with an exogenous Notch intracellular domain (NICD) that does not encode a full-length Notch protein. The claim structure specifies the preparation process of the exogenous cells and the introduction into the central nervous system.
Inducing MMP-9 expression in the central nervous system by introducing exogenous cells
A method for inducing expression of matrix metalloproteinase-9 (MMP-9) in the central nervous system of a subject by introducing exogenous cells into the central nervous system of the subject.
Exogenous cells obtained from marrow adherent stem cells engineered with a non-full-length Notch intracellular domain polynucleotide
Exogenous cells are obtained by providing a culture of marrow adherent stem cells (MSCs), contacting the cell culture with a polynucleotide comprising sequences encoding a Notch intracellular domain (NICD) wherein the polynucleotide does not encode a full-length Notch protein, selecting cells that comprise the polynucleotide, and further culturing the selected cells in adherent culture in the absence of selection.
Overall, the independent claim centers on delivering exogenous cells to induce MMP-9 expression in the central nervous system, where the exogenous cells are generated from marrow adherent stem cells by introducing an NICD-encoding polynucleotide that does not encode a full-length Notch protein.
Stated Advantages
Therapeutic benefits in traumatic brain injury without long-term graft persistence.
Biobridge-associated upregulation of matrix metalloproteinase-9 (MMP-9) activity.
Enables endogenous neurogenic cell proliferation, differentiation, and migration from the subventricular zone to the injury site.
Documented Applications
Treating traumatic brain injury (TBI) by transplanting SB623 cells derived from marrow adherent stem cells (MSCs) engineered with exogenous NICD for a biobridge pathway between the subventricular zone and the injured cortex.
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