SAFETY OF MESENCHYMAL STEM CELL ADMINISTRATION TO THE CNS OF RHESUS MACAQUES

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Lysosomal storage diseases are inherited metabolic disorders characterized by an abnormal build-up of various toxic materials in the body's cells as a result of enzyme deficiencies. To date, over 50 of these disorders have been described in humans, which manifest in a wide array of clinical symptoms. Some of these disorders are characterized by abnormal accumulation of storage material in neurons and/or myelin producing cells, causing progressive neurologic deterioration and premature death. Currently, there are no established therapies for treating neurological sequelae associated with lysosomal storage diseases. Therefore, our studies aim to assess the safety, feasibility and efficacy of adult stem cell administration to the CNS for treating these complications. 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 using stereotaxic coordinates determined by MRI. Prior to and at various periods up to 1 year post-administration of stem cells the health, development, spontaneous behavior and upper limb motor performance of each transplant recipient will be evaluated using a battery of tests. Additionally, the levels and anatomical distribution of MSCs engrafted in the CNS will be evaluated using a real-time PCR assay we developed. 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 disease) and their engraftment levels and distribution will be directly correlated with levels of reconstituted galactocerebrosidase 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. Collectively, these studies will yield important safety and efficacy data useful for developing MSC-based therapies to treat neurologic sequelae in humans afflicted with storage