Inherited metabolic disorders cause a significant number of brain diseases. A major barrier to treating such diseases is that the inherent nature of the defect results in global distribution of the pathologic lesions within the CNS. This circumstance requires that cells be corrected either throughout the CNS or in key areas where the pathologic consequences are most severe. In this grant we will investigate neural stem cell (NSC)-based approaches to treat the central nervous system (CNS) in neurogenetic disease by delivering a diffusible protein within the brain. The approach is to genetically correct the defect in NSCs in vitro and transplant the corrected cells back into the defective brain. Under the right circumstances, NSCs can migrate within the brain and differentiate into all three major lineages of brain cells. As a test system, we will use a B- glucuronidase (GUSB) deficient mouse, which is a model for human lysosomal storage diseases (LSD). There are >50 individual LSDs and they are responsible for approximately 20% of all inherited childhood genetic diseases that affect the CNS. A common treatment strategy can be used, in principle, for >90% of the LSD's. It is based on the observation that lysosomal enzymes can be secreted from genetically corrected cells, diffuse through tissue, and can be taken up by mutant cells to restore the missing enzymatic activity. Thus, delivery of the modified NSC's to only a fraction of the brain may be able to rescue a large amount of brain tissue. To achieve global delivery of the therapeutic enzyme, the transplanted cells need to be dispersed within the three dimensional space of the brain. We have demonstrated that gene therapy can work in the brains of the GUSB-deficient mice using a clonal cell line. However, there are substantial barriers to achieving permanent and complete correction, particularly in reaching the global lesions in the much larger human brain. We propose to investigate: 1) the transplantation properties and vector gene expression in primary murine NSC's as a model for autologous correction (en vivo gene therapy); 2) potential strategies to increase the migration of the NSC's away from the injection site; and 3) the effectiveness of the treatment on the neuropathology and the safety of the transplant recipients. Advances in understanding the transplantation properties of NSC's for treatment in this model should have applicability to the whole class of disease. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS056243-02
Application #
7459697
Study Section
Developmental Brain Disorders Study Section (DBD)
Program Officer
Owens, David F
Project Start
2007-07-15
Project End
2012-06-30
Budget Start
2008-07-01
Budget End
2009-06-30
Support Year
2
Fiscal Year
2008
Total Cost
$356,374
Indirect Cost
Name
Children's Hospital of Philadelphia
Department
Type
DUNS #
073757627
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Kumar, Manoj; Nasrallah, Ilya M; Kim, Sungheon et al. (2014) High-resolution magnetic resonance microscopy and diffusion tensor imaging to assess brain structural abnormalities in the murine mucopolysaccharidosis VII model. J Neuropathol Exp Neurol 73:39-49
Simonato, Michele; Bennett, Jean; Boulis, Nicholas M et al. (2013) Progress in gene therapy for neurological disorders. Nat Rev Neurol 9:298
Chaubey, Sushma; Wolfe, John H (2013) Transplantation of CD15-enriched murine neural stem cells increases total engraftment and shifts differentiation toward the oligodendrocyte lineage. Stem Cells Transl Med 2:444-54
Schwartz, Lynnae; Spitsin, Sergei V; Meshki, John et al. (2013) Substance P enhances HIV-1 infection in human fetal brain cell cultures expressing full-length neurokinin-1 receptor. J Neurovirol 19:219-27
Weerakkody, Tanya N; Patel, Tapan P; Yue, Cuiyong et al. (2013) Engraftment of nonintegrating neural stem cells differentially perturbs cortical activity in a dose-dependent manner. Mol Ther 21:2258-67
Walton, Raquel M; Parmentier, Thomas; Wolfe, John H (2013) Postnatal neural precursor cell regions in the rostral subventricular zone, hippocampal subgranular zone and cerebellum of the dog (Canis lupus familiaris). Histochem Cell Biol 139:415-29
Simonato, Michele; Bennett, Jean; Boulis, Nicholas M et al. (2013) Progress in gene therapy for neurological disorders. Nat Rev Neurol 9:277-91
Parente, Michael K; Rozen, Ramona; Cearley, Cassia N et al. (2012) Dysregulation of gene expression in a lysosomal storage disease varies between brain regions implicating unexpected mechanisms of neuropathology. PLoS One 7:e32419
Wolfe, John H (2009) Gene therapy in large animal models of human genetic diseases. Introduction. ILAR J 50:107-11
Walton, Raquel M; Magnitsky, Sergey G; Seiler, Gabriela S et al. (2008) Transplantation and magnetic resonance imaging of canine neural progenitor cell grafts in the postnatal dog brain. J Neuropathol Exp Neurol 67:954-62

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