Abstract

Approximately one in 5000 males in human population suffers from coagulation disorder, hemophilia A. This disease is primarily caused by deficiency in the factor VIII gene located in the X-chromosome and is difficult to treat by conventional medicine. Current treatment of hemophilia A by intravenous infusion of factor VIII concentrates is very costly and has a potential side effect of developing inhibitors. Gene therapy, on the other hand, can potentially prevent these limitations of current treatments. Although recombinant adeno-associated virus (rAAV) vectors are promising for deliver factor VIII gene, applying AAV vector technology to Hemophilia A lagged behind other genetic diseases because of this size constraint (limited to ~5kb). To improve factor VIII gene delivery utilizing rAAV vectors, we have developed novel engineered factor VIII molecules for use in both dual vectors and single vector strategy.
The specific aims for this proposal are: 1). To develop a Factor VIII heavy chain molecule efficient for secretion;2). To develop and characterize a novel mini factor VIII gene for rAAV delivery;3). To analyze immune responses against the engineered factor VIII transgene products. The success of this proposal may lead to a clinical trial of hemophilia A using AAV vectors.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL084381-02
Application #
7546648
Study Section
Gene and Drug Delivery Systems Study Section (GDD)
Program Officer
Link, Rebecca P
Project Start
2008-01-01
Project End
2009-02-06
Budget Start
2009-01-01
Budget End
2009-02-06
Support Year
2
Fiscal Year
2009
Total Cost
$74,025
Indirect Cost

  Institution

Name
Children's Hospital of Philadelphia
Department
Type
DUNS #
073757627
City
Philadelphia
State
PA
Country
United States
Zip Code
19104

  Publications

Xiao, Weidong; Gao, Guangping; Ling, Chen et al. (2018) Impact of neutralizing antibodies against AAV is a key consideration in gene transfer to nonhuman primates. Nat Med 24:699
Zhang, Wei; Mao, Jianhua; Shen, Yan et al. (2018) Evaluation of the activity levels of rat FVIII and human FVIII delivered by adeno-associated viral vectors both in vitro and in vivo. Blood Cells Mol Dis 73:47-54
Gashash, Ebtesam A; Aloor, Arya; Li, Dong et al. (2017) An Insight into Glyco-Microheterogeneity of Plasma von Willebrand Factor by Mass Spectrometry. J Proteome Res 16:3348-3362
Wang, Qizhao; Dong, Biao; Pokiniewski, Katie A et al. (2017) Syngeneic AAV Pseudo-particles Potentiate Gene Transduction of AAV Vectors. Mol Ther Methods Clin Dev 4:149-158
Wang, Qizhao; Wu, Zhongren; Zhang, Junping et al. (2017) A Robust System for Production of Superabundant VP1 Recombinant AAV Vectors. Mol Ther Methods Clin Dev 7:146-156
Arango-Argoty, Gustavo; Singh, Gargi; Heath, Lenwood S et al. (2016) MetaStorm: A Public Resource for Customizable Metagenomics Annotation. PLoS One 11:e0162442
Wang, Qizhao; Firrman, Jenni; Wu, Zhongren et al. (2016) High-Density Recombinant Adeno-Associated Viral Particles are Competent Vectors for In Vivo Transduction. Hum Gene Ther 27:971-981
Wang, Q; Dong, B; Firrman, J et al. (2016) Evaluation of the biological differences of canine and human factor VIII in gene delivery: implications in human hemophilia treatment. Gene Ther 23:597-605
Kelich, Joseph M; Ma, Jiong; Dong, Biao et al. (2015) Super-resolution imaging of nuclear import of adeno-associated virus in live cells. Mol Ther Methods Clin Dev 2:15047
Moore, Andrea R; Dong, Biao; Chen, Lingxia et al. (2015) Vaccinia virus as a subhelper for AAV replication and packaging. Mol Ther Methods Clin Dev 2:15044

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