Correction of Hurler syndrome by multipotent stem cells

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DESCRIPTION (provided by applicant): Novel approaches based on pathophysiologic mechanisms are needed to treat progressive neurological dysfunction and mental retardation in Hurler syndrome (MPS I). Our group has identified a multipotent adult progenitor cell (MAPC) in human and rodent bone marrow (BM), which differentiates in vitro and in vivo into all three embryonic lineages, including neuronal and glial cells (Blood 98:2615, 2001; Nature 418:41, 2002). MAPC implanted into adult rodent brains engraft, acquire neuronal and glial markers and ameliorate ischemic neurological dysfunction. MAPC may be ideal for neural tissue reconstitution/gene delivery, as they 1) are obtained from a small BM sample and proliferate without senescence 2) are efficiently transduced and express genes without losing stem cell potential 3) are free from ethical issues of embryonic/fetal tissues. During an R03 grant, we found that 1) structurally abnormal heparan sulfates (HS) in Hurler MAPC have defective binding interactions with FGF-2, thus impairing its biological activity on MAPC survival, proliferation and neural differentiation 2) normal MAPC provide trophic and corrective signals to Hurler MAPC 3) gene expression of proteoglycans (PGs), glycosaminoglycan (GAG) metabolic enzymes, cytokines and morphogens is altered in Hurler MAPC. Separately, our group found severe neuropathological and behavioral abnormalities in a murine knockout model of MPS I. We hypothesize that 1) the structural and functional abnormalities of HS contribute to the neuronal pathophysiology of Hurler syndrome by perturbing the biological activity of critical cytokines and by secondarily modulating gene expression, and 2) following intra-ventricular transplantation, normal human MAPC will engraft in the brain of neonatal immunodeficient (NOD-SCID)-MPS I mice and ameliorate behavioral abnormalities. Specific Aim (SA) 1: Compare the structure and function of HS from normal and Hurler MAPC and murine brain tissue. SA2: Test the secondary effects of accumulated GAGs and oligosaccharides on HS biosynthesis and gene expression in Hurler MAPC. SA3: Examine if the neuropathology and behavioral dysfunction in NOD-SCID-MPS I mice can be corrected by intracerebroventricular transplantation of normal human MAPC. If MAPC transplantation is of benefit in the Hurler model, similar strategies may be developed for treating diverse neurodegenerative disorders.