Gene therapy for treatment of hemophilia A

描述（由申请人提供）：基因治疗有望成为一种单一疗法

DESCRIPTION (provided by applicant): Gene therapy promises to be a singular advance in the treatment of both acquired and genetic diseases at the most fundamental levels of pathology. Hemophilia A patients express insufficient levels of factor VIII. This protein is primarily expressed in the liver. A novel method of intravascular injection of plasmid DNA expression vectors results in highly efficient transfection of hepatocytes. This project will use this simple and innovative gene transfer approach to develop a gene therapy protocol for the treatment of hemophilia A. Despite the promise of this non-viral gene therapy approach, there are two problems that have to be solved for it to be clinically-viable: 1) current plasmid DNA expression vectors do not result in long term expression; 2) gene transfer is often accompanied by hepatocyte damage. In this Phase I application, experiments are proposed to developed plasmid DNA expression vectors that will enable long-term expression of human factor VIII (hF8). We will generate vectors with liver specific promoters and hF8 genomic sequences. Recently, a similar plasmid DNA expression vector was described that expressed human factor IX for more than 6 months. Phase II will focus on developing the surgical approaches for delivering the naked pDNA to the liver with minimal liver toxicity, using catheter-based techniques frequently used in clinical practice. These experiments will generate the pre-clinical data required for a human trial application. These gene delivery techniques can also be used for the development of gene therapy protocols for applications such as other clotting factor abnormalities, phenylketonuria, alpha 1 -antitrypsin deficiency, complement factor deficiencies, and other hematologic or metabolic disorders. PROPOSED COMMERCIAL APPLICATION: NOT AVAILABLE