Pre-Clinical Trial of MSC-Based Therapy for CNS Disease

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DESCRIPTION (provided by applicant): This proposal aims to assess in a relevant animal model the safety, feasibility and efficacy of adult stem cell administration to the CNS for treating neurological sequelae associated with lysosomal storage diseases. Specifically, adult stem cells derived from bone marrow, referred to as mesenchymal stem cells (MSCs) will be injected unilaterally into the caudate putamen of infant rhesus macaques (Macaca mulatta) using stereotaxic coordinates determined by MRI. Prior to and at various periods up to 1 year post-transplantation, the health, development, behavior as well as cognitive and motor skills of each transplant recipient will be evaluated using a battery of age appropriate tests and compared to sham-operated animals or normative control data. Additionally, the levels and anatomical distribution of male MSCs engrafted in the CNS of female transplant recipients will be evaluated using a real-time PCR assay we developed that targets sequences in the Macaca sp. Y chromosome. To confirm the real-time PCR data engrafted MSCs will be visualized in brain sections by immunofluorescent staining or FISH and counted using modern stereological techniques. Correlating MSC engraftment in brain with long-term affects on health, development, behavior and motor function will directly assess the safety and feasibility of intracranial MSC administration. Subsequently, MSCs will be injected into the CNS of infant macaques afflicted with globoid cell leukodystrophy (Krabbe's Disease). The latter is characterized by a lack of galactocerebrosidase (GALC) activity, which results in abnormal accumulation of storage material in oligodendrocytes causing progressive demyelination in the nervous system. In these studies MSC engraftment levels and distribution will be directly correlated with levels of expressed GALC mRNA and enzyme activity throughout the CNS. Furthermore, affects on disease progression will be evaluated using biochemical and histological methods as well as behavioral and motor performance tests. Consequently, this phase of the study will directly evaluate the therapeutic efficacy of MSC administration. Collectively, these proposed studies will yield important pre-clinical data in a relevant animal model that will be essential for developing stem cell-based therapies to treat neurological sequelae in human infants and children afflicted with various lysosomal storage diseases.