Glial progenitor cells and the neural stem cells from which they derive may be isolated and transplanted into myelin-deficient hosts, as a means of introducing new oligodendrocytes able to myelinate host axons (Yandava et al., “Global Cell Replacement is Feasible Via Neural Stem Cell Transplantation: Evidence From the Dysmyelinated Shiverer Mouse Brain,” Proc Natl Acad Sci USA 96:7029-34 (1999); Learish et al., “Intraventricular Transplantation of Oligodendrocyte Progenitors Into a Fetal Myelin Mutant Results in Widespread Formation of Myelin,” Ann Neurol 46:716-22 (1999); Archer et al., “Myelination of the Canine Central Nervous System by Glial Cell Transplantation: A Model for Repair of Human Myelin Disease,” Nature Medicine 3:54-59 (1997); Mitome et al., “Towards the Reconstruction of Central Nervous System White Matter Using Neural Precursor Cells,” Brain 124:2147-61 (2001); Eftekharpour et al., “Myelination of Congenitally Dysmyelinated Spinal Cord Axons by Adult Neural Precursor Cells Results in Formation of Nodes of Ranvier and Improved Axonal Conduction,” J Neuroscience 27:3416-3428 (2007)). Applicants have previously noted that enriched preparations of human glial progenitor cells, when engrafted into the neonatal shiverer mouse, a mutant that lacks full-length myelin basic protein (Roach et al., “Chromosomal Mapping of Mouse Myelin Basic Protein Gene and Structure and Transcription of the Partially Deleted Gene in Shiverer Mutant Mice,” Cell 42:149-55 (1985)), generate substantial myelin in these otherwise unmyelinated recipients (Windrem et al., “Fetal and Adult Human Oligodendrocyte Progenitor Cell Isolates Myelinate the Congenitally Dysmyelinated Brain,” Nature Medicine 10:93-97 (2004)). However, the potential utility of this approach to the development of clinical remyelination strategies has been unclear, since previous studies have failed to note significant brainstem, cerebellar or spinal engraftment from intracerebral grafts, and no effect on disease phenotype or survival has yet been reported in hypomyelinated mice as a consequence of progenitor cell transplantation (reviewed in Keyoung et al., “Glial Progenitor-Based Repair of Demyelinating Neurological Diseases,” Neurosurg. Clin. NA 18:93-104 (2007) and Goldman, S. A., “Stem and Progenitor Cell-Based Therapy of the Human Central Nervous System,” Nature Biotech. 23:862-871 (2005)). Indeed, applicants' initial study of the efficacy of isolated human glial progenitors revealed no overt effect of cell transplantation on either the condition or fate of the engrafted recipients; despite widespread forebrain myelination, the transplanted mice typically died between 18 and 20 weeks of age, just as did unengrafted shiverers.
The present invention is directed to overcoming these and other deficiencies in the art.
USPTO Backgrounds
USPTO Backgrounds