Owing to the structural and functional complexity and relative inaccessibility of the central nervous system (CNS), most chronic neurologic and neurodegenerative disorders lack effective treatments, and, therefore, require the development of novel therapeutic approaches including gene therapy and cellular therapy. Krabbe disease, or globoid cell leukodystrophy (GLD), is an inherited, recessive disorder affecting the peripheral nervous system (PNS) and the CNS caused by defects of the lysosomal enzyme galactocerebrosidase (GALC). This enzyme catalyzes the lysosomal hydrolysis of galactosylceramide and galactosylsphingosine (psychosine). The enzyme defect causes a series of pathological changes including demyelination. This autosomal recessive disease affects humans and animals including dogs, mice, and rhesus monkeys. The goal of the proposed project is to explore gene therapy strategies for Krabbe disease using improved lentivirus-based gene and protein delivery strategies. These strategies will initially be tested in rats and later on extended to mice and rhesus monkeys affected with GLD.
The Specific Aims are: 1. To modify HIV-l-based lentiviral vectors for improved transgene delivery and expression in the CNS. These vectors will harbor constitutive as well as regulatable promoters. Vectors will be pseudotyped with the vesicular stomatitis virus (VSV)-G glycoprotein. Pseudotypes involving the Mokola virus G glycoprotein will also be tested with a view toward distributing such vectors more globally in the CNS. Vector delivery will be carried out by direct brain injection. 2. To investigate protein transduction mechanisms with a view toward facilitating the global delivery in the CNS of GALC tagged with the transduction domain of HIV-1 TAT, the membrane translocating hydrophobic sequence from fibroblast growth factor or the herpes simplex virus VP22 protein. 3. To use lentiviral vectors to transfer the GALC cDNA into the brains of mice and rhesus monkeys affected with GLD to evaluate the capacity of such vectors to correct the GLD defect and histological abnormalities.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS044832-02
Application #
6721401
Study Section
Medical Biochemistry Study Section (MEDB)
Program Officer
Tagle, Danilo A
Project Start
2003-04-01
Project End
2006-03-31
Budget Start
2004-04-01
Budget End
2005-03-31
Support Year
2
Fiscal Year
2004
Total Cost
$236,075
Indirect Cost
Name
Louisiana State University Hsc New Orleans
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
782627814
City
New Orleans
State
LA
Country
United States
Zip Code
70112
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