Pelizaeus-Merzbacher disease (PMD) is a severe X-linked pediatric neurodegenerative disorder impacting myelination in the central nervous system. PMD results from mutations in the PLP1 gene which encodes the most prevalent myelin protein of the central nervous system. PMD exhibits a spectrum of clinical phenotypes that reflect wide genotypic heterogeneity, but nearly all forms of the disease result in progressive neurological deterioration and death, often during childhood. With the advent of induced pluripotent stem cell (iPSC) technologies and cell fate reengineering, we have now developed robust methods for generation of patient- specific oligodendrocytes in vitro. This provides new access to model the phenotypic and genotypic spectra within PMD. We have generated a large comprehensive panel of characterized iPSC lines from PMD patients that spans the full genotypic and phenotypic spectrum of the disorder. In this application we will focus on the patient-specific molecular and cellular deficits in PMD patient oligodendrocytes and provide platforms for testing of therapeutics.
Aim 1 will use the robust human iPSC-derived oligodendrocyte differentiation protocols that we have developed as a phenotyping platform for examining PMD patient oligodendrocyte dysfunction and assessing the ability of clinically-relevant pharmacologic therapies to rescue individual phenotypes in vitro.
Aim 2 will use an approach by which we can produce humanized chimeric mice whose oligodendrocytes and myelin have been largely replaced by human iPSC-derived oligodendroglia. Combining this technology with PMD iPSC lines from our panel will enable us to generate patient-specific PMD glial chimeras and examine oligodendrocyte dysfunction in vivo.
In Aim 3 we will test if genetically-corrected PMD iPSC-derived OPCs show restored myelination capacity in glial chimeric mice. Together, these studies should provide us new insight into the cell and molecular deficits driving the pathogenesis of PMD. Our goal is to establish in vitro and in vivo platforms for the modeling and treatment of PMD, while providing a broad strategy for the treatment of hereditary disorders of myelin.
Pelizaeus-Merzbacher disease (PMD) is a rare but severe heritable disorder caused by mutations in the PLP1 gene. Patients exhibit phenotypic and genetic variability but show significant neurological dysfunction and often death during childhood. The advent of induced pluripotent stem cell and cell fate engineering technologies provides us with a new method to model myelin diseases such as PMD in patient-derived cells. This study aims to discover the etiology of PMD and create a platform for developing molecular, genetic, and cellular therapeutics for this and other myelin diseases.
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