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 #
5R01HL130871-04
Application #
9609480
Study Section
Gene and Drug Delivery Systems Study Section (GDD)
Program Officer
Sarkar, Rita
Project Start
2016-01-01
Project End
2019-12-31
Budget Start
2019-01-01
Budget End
2019-12-31
Support Year
4
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Temple University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
057123192
City
Philadelphia
State
PA
Country
United States
Zip Code
19122
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