The long term goal of this Project is to develop gene therapy methods for the treatment of neural disorders. Two types of neurological dysfunction will he investigated: spinal cord lesions and autosomal dominant retinitis pigmentosa (ADRP). The first is a complex problem likely to require multiple therapeutic strategies. It is expected that gene therapy of spinal cord lesions will the introduction of multiple genes using vectors that can promote tissue specific transgene expression. This Program will assess the effect of two classes of gene in rat spinal cord lesion models. The neurotrophic factors GDNF and NT-3 will be tested both in vivo and ex vivo in conjunction with spinal cord grafts to determine if they can promote neuronal rescue. The second disease (ADRP) was chosen for this Program because it is a well characterized single gene defect which presents inherently simpler therapeutic problems. Ribozymes capable of downregulating the dominant mutation will be tested in newly developed rat models of retinitis pigmentosa to determine if clinically relevant improvement can he achieved in the course of the disease. Finally, all of the projects will focus on the use of one kind of viral vector, adeno-associated virus (AAV). AAV was chosen because the preliminary data assembled by the Project members suggests that AAV is likely to be successful in directing expression of transgenes in the terminally differentiated tissues of the retina and spinal cord for extended time periods and because it holds the promise of tissue specific gene expression. However, the Program recognizes the fact that AAV still has significant technical difficulties associated with it and these are also addressed. In addition, the Program has established a Vector Core Laboratory which will supply vectors of uniform and reproducible quality to all subprojects, construct modified versions of existing marker genes and genes of potential therapeutic value, and develop better purification methods. The Vector Core also will serve as mechanism to insure rapid exchange of information among all subprojects.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Program Projects (P01)
Project #
5P01NS036302-04
Application #
6330503
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Program Officer
Chiu, Arlene Y
Project Start
1997-12-01
Project End
2002-11-30
Budget Start
2000-12-01
Budget End
2001-11-30
Support Year
4
Fiscal Year
2001
Total Cost
$915,023
Indirect Cost
Name
University of Florida
Department
Genetics
Type
Schools of Medicine
DUNS #
073130411
City
Gainesville
State
FL
Country
United States
Zip Code
32611
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Deng, Wen-Tao; Dinculescu, Astra; Li, Qiuhong et al. (2012) Tyrosine-mutant AAV8 delivery of human MERTK provides long-term retinal preservation in RCS rats. Invest Ophthalmol Vis Sci 53:1895-904
Wu, Ke; Li, Shoudong; Bodhinathan, Karthik et al. (2012) Enhanced expression of Pctk1, Tcf12 and Ccnd1 in hippocampus of rats: Impact on cognitive function, synaptic plasticity and pathology. Neurobiol Learn Mem 97:69-80
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Pang, Ji-jing; Dai, Xufeng; Boye, Shannon E et al. (2011) Long-term retinal function and structure rescue using capsid mutant AAV8 vector in the rd10 mouse, a model of recessive retinitis pigmentosa. Mol Ther 19:234-42
Pang, J; Boye, S E; Lei, B et al. (2010) Self-complementary AAV-mediated gene therapy restores cone function and prevents cone degeneration in two models of Rpe65 deficiency. Gene Ther 17:815-26
Gorbatyuk, Oleg S; Li, Shoudong; Nguyen, Frederic Nha et al. (2010) ?-Synuclein expression in rat substantia nigra suppresses phospholipase D2 toxicity and nigral neurodegeneration. Mol Ther 18:1758-68
Gorbatyuk, Oleg S; Li, Shoudong; Nash, Kevin et al. (2010) In vivo RNAi-mediated alpha-synuclein silencing induces nigrostriatal degeneration. Mol Ther 18:1450-7
Pang, Ji-Jing; Alexander, John; Lei, Bo et al. (2010) Achromatopsia as a potential candidate for gene therapy. Adv Exp Med Biol 664:639-46
Peden, Carmen S; Manfredsson, Fredric P; Reimsnider, Sharon K et al. (2009) Striatal readministration of rAAV vectors reveals an immune response against AAV2 capsids that can be circumvented. Mol Ther 17:524-37

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