Myelination of the central nervous system remains an elusive goal for treating disorders such as multiple sclerosis and leukodystrophies. A number of recent studies have laid the foundation and catalyzed current enthusiasm for the use of lineage conversion as a potential regenerative therapy for many neurological disorders. However, transplantation and functional integration of fully mature cells such as neurons and oligodendrocytes has clear limitations, therefore expandable somatic progenitors are a sought after target for cell-based therapies. It is with the advent of cell based therapies that autologously derived oligodendrocyte progenitor cells hold promise for potentially treating human leukodystrophies. For this reason, there exists a clinical need to derive autologous oligodendrocytes from non-neural cells. However, in genetic related dysmyelinating disease, functional oligodendrocyte progenitor cells cannot be directly reprogrammed from non- neural cells. This issue brings to light the need for gene-therapy coupled with cell based therapies for treating genetic related myelin diseases. I hypothesized that myelin basic protein deficient mice (shiverer, Mbpshi/shi), a model of human congenital leukodystrophies, can be rescued through transplantation of autologously derived, gene corrected oligodendrocyte progenitor cells from fibroblasts and induced pluripotent stem (iPS) cells for the myelination of the central nervous system. To address this hypothesis I propose to (1) generate gene- corrected, functional induced oligodendrocyte progenitor cells from shiverer (Mbpshi/shi) fibroblasts and (2) gene-correct and directly differentiate shiverer (Mbpshi/shi) iPS cells to functional oligodendrocyte progenitor cells. Recent advances have demonstrated the successful modulation of transcription factor profiles to reprogram patient specific fibroblasts into cell types of interest. With this knowledge I can modulate transcription factor profiles to change the state of the cell to generate a population of oligodendrocyte progenitor cells or induced pluripotent stem cells which have the capability of being directly differentiated into oligodendrocyte progenitor cells. In addition, I propose to genetically correct the autologous starting populations by introducing a bacterial artificial chromosome that contains the full myelin basic protein gene, as wells as its endogenous regulatory elements. Through these methods I propose to generate a population of gene-corrected autologously derived oligodendrocyte progenitor cells that when injected in vivo into the host shiverer (Mbpshi/shi) mouse model leads to the functional myelination of the once hypomyelinated central nervous system. Thus for the first time a patient-specific population of oligodendrocyte progenitor cells can be generated, that have been engineered to lack disease causing mutations, for the potential treatment of genetic related myelin diseases.
There are currently no treatments or cures for the millions of individuals who are afflicted with myelin- associated disorders such as multiple sclerosis. This project aims to devise methods for generating patient- specific, disease-associated cell types from a patient's own skin cells. This significant achievement represents a conceptual and technological advancement toward providing individualized treatment for those whose lives are affected by myelin related diseases.
|Najm, Fadi J; Lager, Angela M; Zaremba, Anita et al. (2013) Transcription factor-mediated reprogramming of fibroblasts to expandable, myelinogenic oligodendrocyte progenitor cells. Nat Biotechnol 31:426-33|