Abstract

There has been good progress made in the area of gene therapy for hemophilia during the past 5 years. The goal is to continue our studies towards hepatic gene transfer into the liver with the goal of developing a curative therapy for hemophilias A and B. Our laboratory is interested in comparing three promising viral vectors for hepatic gene transfer for hemophilia. We plan to do studies to further understand the biology of the vectors as it relates to transduction of hepatocytes in vivo. This information will be used to develop preclinical trials for these vectors by testing the most promising approaches in two animal models, mouse and canine hemophilias.
The aims are to: (1) Compare the safety and hepatic transduction efficiencies of mouse Moloney, human foamy, and human lenti viruses, and determine their abilities to express clotting factors in vivo. (2) Further develop rAAV vectors for hepatic gene therapy for hemophilia. (3) Determine the potential use of an Adenoviral/AAV hybrid virus that is devoid of all viral genes for hemophilia gene therapy. We believe these studies will further our understanding of three important classes of viral vectors for hepatic gene transfer and develop the principles required for a clinical trial for the treatment of hemophilias A and B.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL064274-03
Application #
6527311
Study Section
Medical Biochemistry Study Section (MEDB)
Program Officer
Link, Rebecca P
Project Start
2000-09-01
Project End
2004-08-31
Budget Start
2002-09-01
Budget End
2003-08-31
Support Year
3
Fiscal Year
2002
Total Cost
$439,648
Indirect Cost

  Institution

Name
Stanford University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
800771545
City
Stanford
State
CA
Country
United States
Zip Code
94305

  Publications

Valdmanis, Paul N; Kay, Mark A (2017) Future of rAAV Gene Therapy: Platform for RNAi, Gene Editing, and Beyond. Hum Gene Ther 28:361-372
Borel, Florie; Tang, Qiushi; Gernoux, Gwladys et al. (2017) Survival Advantage of Both Human Hepatocyte Xenografts and Genome-Edited Hepatocytes for Treatment of ?-1 Antitrypsin Deficiency. Mol Ther 25:2477-2489
Porro, Fabiola; Bortolussi, Giulia; Barzel, Adi et al. (2017) Promoterless gene targeting without nucleases rescues lethality of a Crigler-Najjar syndrome mouse model. EMBO Mol Med 9:1346-1355
Puzzo, Francesco; Colella, Pasqualina; Biferi, Maria G et al. (2017) Rescue of Pompe disease in mice by AAV-mediated liver delivery of secretable acid ?-glucosidase. Sci Transl Med 9:
Lu, Jiamiao; Williams, James A; Luke, Jeremy et al. (2017) A 5' Noncoding Exon Containing Engineered Intron Enhances Transgene Expression from Recombinant AAV Vectors in vivo. Hum Gene Ther 28:125-134
Lu, Jiamiao; Zhang, Feijie; Fire, Andrew Z et al. (2017) Sequence-Modified Antibiotic Resistance Genes Provide Sustained Plasmid-Mediated Transgene Expression in Mammals. Mol Ther 25:1187-1198
Winters, Ian P; Chiou, Shin-Heng; Paulk, Nicole K et al. (2017) Multiplexed in vivo homology-directed repair and tumor barcoding enables parallel quantification of Kras variant oncogenicity. Nat Commun 8:2053
Wang, Yongming; Pryputniewicz-Dobrinska, Diana; Nagy, Enikö Éva et al. (2017) Regulated complex assembly safeguards the fidelity of Sleeping Beauty transposition. Nucleic Acids Res 45:311-326
Chu, Jun; Oh, Younghee; Sens, Alex et al. (2016) A bright cyan-excitable orange fluorescent protein facilitates dual-emission microscopy and enhances bioluminescence imaging in vivo. Nat Biotechnol 34:760-7
Nygaard, Sean; Barzel, Adi; Haft, Annelise et al. (2016) A universal system to select gene-modified hepatocytes in vivo. Sci Transl Med 8:342ra79

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