Abstract

The overall objective of the proposed research is to develop gene transfer strategies designed to overcome the three main obstacles to effective neural gene therapy for neuropathic lysosomal storage disease (LSD) with mental retardation. These obstacles are: 1) global neural delivery, 2) neuronal-specific targeting, and 3) continuous neuronal expression. Relevant to this proposal are out previous observations: 1) that the overexpression of human lysosomal enzymes results in their selective secretion, 2) that covalent coupling of neuronotropic polypeptides to lysosomal enzymes markedly enhanced their uptake and endosomal internalization in cultured neurons, and 3) that the blood brain barrier can be transiently and safely opened for neural delivery of macromolecules or enzymes in cats by infusion of hyperosmolar mannitol. The optimal neuronal-targeted overexpression constructs and neural delivery strategies will be assessed in animal models of human LSD in Project 4 of this Program Project.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Program Projects (P01)
Project #
5P01HD032654-03
Application #
6241293
Study Section
Project Start
1996-12-01
Project End
1997-11-30
Budget Start
1996-10-01
Budget End
1997-09-30
Support Year
3
Fiscal Year
1997
Total Cost
Indirect Cost

  Institution

Name
Mount Sinai School of Medicine
Department
Type
DUNS #
City
New York
State
NY
Country
United States
Zip Code
10029

  Publications

Miranda, S R; Erlich, S; Friedrich Jr, V L et al. (2000) Hematopoietic stem cell gene therapy leads to marked visceral organ improvements and a delayed onset of neurological abnormalities in the acid sphingomyelinase deficient mouse model of Niemann-Pick disease. Gene Ther 7:1768-76
Schuchman, E H; Erlich, S; Miranda, S R et al. (2000) Fluorescence-based selection of gene-corrected hematopoietic stem and progenitor cells based on acid sphingomyelinase expression. Methods Enzymol 312:330-8
Miranda, S R; He, X; Simonaro, C M et al. (2000) Infusion of recombinant human acid sphingomyelinase into niemann-pick disease mice leads to visceral, but not neurological, correction of the pathophysiology. FASEB J 14:1988-95
Erlich, S; Miranda, S R; Visser, J W et al. (1999) Fluorescence-based selection of gene-corrected hematopoietic stem and progenitor cells from acid sphingomyelinase-deficient mice: implications for Niemann-Pick disease gene therapy and the development of improved stem cell gene transfer procedures. Blood 93:80-6
Miranda, S R; Erlich, S; Friedrich Jr, V L et al. (1998) Biochemical, pathological, and clinical response to transplantation of normal bone marrow cells into acid sphingomyelinase-deficient mice. Transplantation 65:884-92
Chen, F W; Davies, J P; Ioannou, Y A (1998) Differential gene expression in apoptosis: identification of ribosomal protein 23K, a cell proliferation inhibitor. Mol Genet Metab 64:271-82
Schuchman, E H; Miranda, S R (1997) Niemann-Pick disease: mutation update, genotype/phenotype correlations, and prospects for genetic testing. Genet Test 1:13-9
Davies, J P; Cotter, P D; Ioannou, Y A (1997) Cloning and mapping of human Rab7 and Rab9 cDNA sequences and identification of a Rab9 pseudogene. Genomics 41:131-4
Miranda, S R; Erlich, S; Visser, J W et al. (1997) Bone marrow transplantation in acid sphingomyelinase-deficient mice: engraftment and cell migration into the brain as a function of radiation, age, and phenotype. Blood 90:444-52
Ioannou, Y A; Chen, F W (1996) Quantitation of DNA fragmentation in apoptosis. Nucleic Acids Res 24:992-3

Showing the most recent 10 out of 11 publications