(Applicant?s Abstract) A multi-investigator, multi-center research/clinical plan is proposed to develop a viral vector-based gene therapy for RPE65 Leber congenital amaurosis (LCA), to complete preclinical safety testing for an Investigational New Drug (IND) submission to the FDA and to begin Phase I/II clinical testing. Seven coordinated modules are described, each with a distinct set of specific aims that contributes in a unique and complimentary way towards the therapeutic goal. Module 1, RPE65 Vector Production will improve AAV vector production for the LCA clinical trial and will provide research and GMP grade vectors for other modules. Module 2, RPE65 Vector improvement will enhance the in vivo efficiency and specificity of Rpe65 gene delivery/expression in RPE cells in animal models by promoter and vector modifications. Module3, RPE65 Mouse Studies will optimize the therapeutic effect of viral (AAV and Lentivirus) vector-delivered RPE65 genes and evaluate any toxic effects in the Rpe65 knock out mouse. Module 4, RPE65 Canine Studies will evaluate vector administration options on the therapeutic outcome of RPE65 gene augmentation in the RPE65 mutant dog. Module 5, RPE65 LCA Human Studies will identify RPE65 LCA patients suitable for entry into a Phase I/II gene therapy trial and develop standardized trial outcome measures. Module 6, RPE65 LCA Clinical Trial, has two aspects: 6A, Pre-clinical Testing and IND Development, will determine the potential for human toxicity and the range of efficacious doses of subretinal AAV-RPE65 in animal models and develop an FDA approved clinical protocol for 613; 6B, Phase IM Trial will evaluate the safety and preliminary efficacy of AAVRPE65 gene replacement therapy for RPE65 LCA-The basic science Modules 1, 2, 3, and 4. and the clinical screening Module 5 also develop information that feeds into the preclinical toxicity study, Module 6A- Data generated in the first 3 years by these modules will help guide the clinical trial design of Module 6B that is scheduled to begin in year 3/4. The University of Florida leads this collaboration with the University of Pennsylvania and Cornell University. The Universities of Iowa and Washington are subcontracting collaborators.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Cooperative Clinical Research--Cooperative Agreements (U10)
Project #
5U10EY013729-05
Application #
6951890
Study Section
Special Emphasis Panel (ZEY1-VSN (03))
Program Officer
Dudley, Peter A
Project Start
2001-09-30
Project End
2007-07-31
Budget Start
2005-08-01
Budget End
2007-07-31
Support Year
5
Fiscal Year
2005
Total Cost
$2,144,684
Indirect Cost
Name
University of Florida
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611
Weleber, Richard G; Pennesi, Mark E; Wilson, David J et al. (2016) Results at 2 Years after Gene Therapy for RPE65-Deficient Leber Congenital Amaurosis and Severe Early-Childhood-Onset Retinal Dystrophy. Ophthalmology 123:1606-20
Jacobson, Samuel G; Cideciyan, Artur V; Roman, Alejandro J et al. (2015) Improvement and decline in vision with gene therapy in childhood blindness. N Engl J Med 372:1920-6
Dai, Xufeng; Han, Juanjuan; Qi, Yan et al. (2014) AAV-mediated lysophosphatidylcholine acyltransferase 1 (Lpcat1) gene replacement therapy rescues retinal degeneration in rd11 mice. Invest Ophthalmol Vis Sci 55:1724-34
Boye, Sanford L; Peshenko, Igor V; Huang, Wei Chieh et al. (2013) AAV-mediated gene therapy in the guanylate cyclase (RetGC1/RetGC2) double knockout mouse model of Leber congenital amaurosis. Hum Gene Ther 24:189-202
Mao, Haoyu; Gorbatyuk, Marina S; Rossmiller, Brian et al. (2012) Long-term rescue of retinal structure and function by rhodopsin RNA replacement with a single adeno-associated viral vector in P23H RHO transgenic mice. Hum Gene Ther 23:356-66
Miyadera, Keiko; Acland, Gregory M; Aguirre, Gustavo D (2012) Genetic and phenotypic variations of inherited retinal diseases in dogs: the power of within- and across-breed studies. Mamm Genome 23:40-61
Boye, Shannon E; Alexander, John J; Boye, Sanford L et al. (2012) The human rhodopsin kinase promoter in an AAV5 vector confers rod- and cone-specific expression in the primate retina. Hum Gene Ther 23:1101-15
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
Doroudchi, M Mehdi; Greenberg, Kenneth P; Liu, Jianwen et al. (2011) Virally delivered channelrhodopsin-2 safely and effectively restores visual function in multiple mouse models of blindness. Mol Ther 19:1220-9
Kaneko, Hiroki; Dridi, Sami; Tarallo, Valeria et al. (2011) DICER1 deficit induces Alu RNA toxicity in age-related macular degeneration. Nature 471:325-30

Showing the most recent 10 out of 75 publications