Methods and compositions for treatment of traumatic brain injury and for modulation of migration of neurogenic cells
Inventors
Borlongan, Cesar V. • Case, Casey C.
Assignees
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Publication Number
US-9828593-B2
Publication Date
2017-11-28
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 invention provides a process in which exogenous cells are implanted at or near an area of brain injury in a subject, where the implanted exogenous cells produce a biological bridge. The implanted exogenous cells do not persist. The implantation induces migration of endogenous neurogenic cells, along the biological bridge, from a neurogenic niche to the area of brain injury, linking a neurogenic niche to an injured cortical region through a temporary structure.
A central aspect of the process is the preparation of the exogenous cells. The exogenous cells are obtained by providing a culture of mesenchymal 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, and selecting cells that comprise the polynucleotide. The selected cells are further cultured in adherent culture in the absence of selection, producing exogenous cells configured to generate the biological bridge or migration pathway after implantation.
In another formulation, the invention describes forming a pathway for cell migration in the brain of a subject by implanting exogenous cells between a neurogenic niche and an area of brain injury. The implanted exogenous cells produce the pathway for cell migration while not persisting, and endogenous neurogenic cells migrate along the pathway from the neurogenic niche to the area of brain injury. The neurogenic niche is described as the subventricular zone in certain embodiments, and additional effects include proliferation of endogenous neurogenic cells.
Claims Coverage
The partial content includes two independent claims (process claims) describing implantation of NICD-expressing MSC-derived exogenous cells that do not persist, but form a biological bridge or a migration pathway that induces migration of endogenous neurogenic cells from a neurogenic niche to an area of brain injury. The independent claims each include a cell-preparation sub-process using a polynucleotide encoding an NICD fragment not encoding full-length Notch protein, selection, and subsequent adherent culture in the absence of selection.
Temporary biological bridge with endogenous neurogenic cell migration
Implanting exogenous cells at or near an area of brain injury such that the implanted exogenous cells produce a biological bridge, the implanted exogenous cells do not persist, and implantation induces migration of endogenous neurogenic cells along the biological bridge from a neurogenic niche to the area of brain injury.
NICD fragment engineering of MSCs without full-length Notch encoding
Obtaining the exogenous cells by providing a culture of MSCs, contacting the cell culture with a polynucleotide 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.
Migration pathway formation between neurogenic niche and injured area
Forming in the brain of a subject a pathway for cell migration by implanting exogenous cells between the neurogenic niche and the area of brain injury so that the implanted exogenous cells produce the pathway, the implanted exogenous cells do not persist, and endogenous neurogenic cells migrate along the pathway from the neurogenic niche to the area of brain injury.
NICD fragment engineering of MSC-derived exogenous cells for pathway formation
Obtaining the exogenous cells by providing a culture of MSCs, contacting the cell culture with a polynucleotide encoding an 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.
Across both independent claims, coverage is centered on implanting exogenous NICD-engineered MSC-derived cells that do not persist, while producing a biological bridge or migration pathway that enables migration of endogenous neurogenic cells from a neurogenic niche to an area of brain injury. The exogenous cells are specifically prepared using a polynucleotide encoding an NICD fragment that does not encode full-length Notch protein, followed by selection and adherent culture in the absence of selection.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Not explicitly described in patent.
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