The cumulative incidence of lysosomal storage diseases has been estimated at 1 in 10,000 live births with 65% demonstrating significant CNS involvement. Systemic therapies can effectively alleviate visceral disease, but the relative impermeability of the human blood-brain barrier has prevented effective correction of CNS deficits. Thus, directed application of enzyme to the brain is required. We hypothesize that recombinant feline immunodeficiency virus (FIV) vectors can be developed and used to complement the enzyme deficiency and accompanying CNS disease. Because many lysosomal enzymes are secreted as well as traffic directly to the lysosome, and uptake of secreted enzyme occurs from transduced and non-transduced cells, delivery to all deficient cells is not required. However, enzyme must reach a significant proportion of the brain for benefit, but optimal methods to accomplish global correction for the LSDs are unknown. Novel envelopes for pseudotyping FIV, identified during the prior award, give us the opportunity to now test how best to achieve this. We will use the beta-glucuronidase deficient (MPS VII) mouse as a model of progressive CNS lysosomal storage disease to address our questions. Two hypotheses will be tested 1) delivery of FIV pseudotyped with envelopes that provide broad transduction profiles or delivery of enzyme from the CSF will reverse functional deficits in the MPS VII mouse brain and 2) an envelope that provides for transduction of resident neuroprogenitor cells will correct functional deficits in the MPS VII brain. Our data will reveal the levels of enzyme required for correction of functional deficits, and the optimal cell targets for achieving persistent global correction of neuropathology and functional restoration in MPS VII brain. The importance of these studies extends to other lysosomal storage diseases affecting the CNS, and many neuropathological conditions for which lentivirus-mediated therapy may be beneficial in future years.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS034568-12
Application #
7151998
Study Section
Developmental Brain Disorders Study Section (DBD)
Program Officer
Tagle, Danilo A
Project Start
1995-02-14
Project End
2009-11-30
Budget Start
2006-12-01
Budget End
2007-11-30
Support Year
12
Fiscal Year
2007
Total Cost
$323,419
Indirect Cost
Name
University of Iowa
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
Tecedor, Luis; Stein, Colleen S; Schultz, Mark L et al. (2013) CLN3 loss disturbs membrane microdomain properties and protein transport in brain endothelial cells. J Neurosci 33:18065-79
Benraiss, Abdellatif; Toner, Michael J; Xu, Qiwu et al. (2013) Sustained mobilization of endogenous neural progenitors delays disease progression in a transgenic model of Huntington's disease. Cell Stem Cell 12:787-99
Hudry, Eloise; Dashkoff, Jonathan; Roe, Alysson D et al. (2013) Gene transfer of human Apoe isoforms results in differential modulation of amyloid deposition and neurotoxicity in mouse brain. Sci Transl Med 5:212ra161
Chen, Yong Hong; Claflin, Kristin; Geoghegan, James C et al. (2012) Sialic acid deposition impairs the utility of AAV9, but not peptide-modified AAVs for brain gene therapy in a mouse model of lysosomal storage disease. Mol Ther 20:1393-9
Schultz, Mark L; Tecedor, Luis; Chang, Michael et al. (2011) Clarifying lysosomal storage diseases. Trends Neurosci 34:401-10
Chen, Yong Hong; Chang, Michael; Davidson, Beverly L (2009) Molecular signatures of disease brain endothelia provide new sites for CNS-directed enzyme therapy. Nat Med 15:1215-8
Chang, Michael; Cooper, Jonathan D; Sleat, David E et al. (2008) Intraventricular enzyme replacement improves disease phenotypes in a mouse model of late infantile neuronal ceroid lipofuscinosis. Mol Ther 16:649-56
Cabrera-Salazar, Mario A; Roskelley, Eric M; Bu, Jie et al. (2007) Timing of therapeutic intervention determines functional and survival outcomes in a mouse model of late infantile batten disease. Mol Ther 15:1782-8
Sands, Mark S; Davidson, Beverly L (2006) Gene therapy for lysosomal storage diseases. Mol Ther 13:839-49
Kang, Yubin; Xie, Litao; Tran, Diane Thi et al. (2005) Persistent expression of factor VIII in vivo following nonprimate lentiviral gene transfer. Blood 106:1552-8

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