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 gene therapy lagged behind other genetic diseases because of this size constraint (limited to ~5kb) and inefficient secretion of factor VIII protein. To improve factor VIII gene delivery utilizing rAAV vectors, we will develop a novel human factor VIII molecules with enhanced expression and secretion.
The specific aims for this proposal are: 1). To develop a human factor VIII molecule with improved secretion and expression; 2). To develop a human factor VIII molecule with enhanced specific activity with minimal amino acid alteration; 3). To optimize the AAV factor VIII packaging and expression cassette and carry out preclinical studies in Hemophilia Animal Model. The success of this proposal may lead to a clinical trial of hemophilia A using AAV vectors.

Public Health Relevance

The completion of this project may lead to novel treatment for hemophilia A patients using a gene therapy strategy. Our work may help reduce the high cost associated with conventional protein therapy and improve the quality of life of hemophilia patients.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
7R01HL130871-05
Application #
10340474
Study Section
Gene and Drug Delivery Systems Study Section (GDD)
Program Officer
Sarkar, Rita
Project Start
2016-01-01
Project End
2021-12-31
Budget Start
2021-02-20
Budget End
2021-12-31
Support Year
5
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Pediatrics
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
Aloor, Arya; Zhang, Junping; Gashash, Ebtesam A et al. (2018) Site-Specific N-Glycosylation on the AAV8 Capsid Protein. Viruses 10:
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
Wang, Minqian; Firrman, Jenni; Zhang, Liqing et al. (2017) Apigenin Impacts the Growth of the Gut Microbiota and Alters the Gene Expression of Enterococcus. Molecules 22:
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
Li, Zhenzhou; Li, Ying; Zhang, Li et al. (2017) Reduced Myocardial Reserve in Young X-Linked Muscular Dystrophy Mice Diagnosed by Two-Dimensional Strain Analysis Combined with Stress Echocardiography. J Am Soc Echocardiogr 30:815-827.e9
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
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
Arango-Argoty, Gustavo; Singh, Gargi; Heath, Lenwood S et al. (2016) MetaStorm: A Public Resource for Customizable Metagenomics Annotation. PLoS One 11:e0162442

Showing the most recent 10 out of 14 publications