Neural Progenitors, Cellular Transplantation and Gene Therapy

Beginning in 1991, a major new area of research in this IDDRC has been the study of neural progenitor or “stem cells.”  This research has included landmark studies of cell fate determination (i.e., identification of external factors and instrinsic factors that regulate the differentiation of neural progenitor cells into neurons, astrocytes and oligodendrocytes). Dr. Greenberg and his colleagues demonstrated that cilliary neurotrophic factor acting through the Jak/STAT pathway plays a key role in the generation of astrocytes (see Science 1997). Drs. Stiles and Rowitch have carried out seminal work leading to the discovery of a family of transcription factors (Neuron 2000, Cell 2002), the Oligs, that specify the differentiation of neural progenitors into oligodendrocytes.  Additional work by Greenberg and his colleagues identified a mechanism by which another transcription factor, neurogenin, supresses the glial fate and promotes neuronal differentiation (Sun et al., Cell 2001).  In addition to these fundamental insights into the mechanisms regulating cell fate determination, IDDRC investigators have been pioneers in efforts to harness the potential of neural progenitors for repairing thedamaged nervous system.  The work has been pursued principally by Drs. Snyder and Macklis (for key initial reports see Cell, 1992; J. Neurosci., 1993; Nature, 1995; PNAS, 1995; Nature, 1995). The potential impact of this research on prevention and treatment of serious neurological disability could be enormous. The initial work utilized a neuron-specific model of cortical neuron depletion, developed by Dr. Macklis, to study development of transplanted, genetically engineered neural progenitors. Remarkably the transplanted cells differentiated and integrated into the lesioned cortex and sent distant appropriate intercortical projections across the corpus callosum. Dr. Snyder’s work showed that the immortalized donor progenitors, upon transplantation, can engraft throughout the neuraxis and develop into “functional” neurons, oligodendroglia and astrocytes. Dr. Snyder then used neural progenitor transplantation to deliver sustained therapeutic levels of the missing gene product ?-glucuronidase directly to and throughout the brain of the Mucopolysaccharidosis Type VII mouse. Enzyme expression by these donor cells as integral brain components resulted in widespread correction of CNS neuropathology in this model of a human metabolic disease that causes mental retardation and is representative of a class of neurogenetic diseases whose CNS manifestations have heretofore been unresponsive to therapy. Dr. Snyder’s subsequent work has extended this exciting therapy to other neurogenetic disorders. This work in the IDDRC Basic Neuroscience Program was followed by parallel development of the use of stem cells in the treatment of muscular dystrophy by Dr. Kunkel in the Genetics Program (Kunkel, Mulligan and Gussoni).