The demonstration of an apparent cure for HIV after allogeneic hematopoietic stem cell transplantation of a leukemia patient in Berlin offers an important proof-of-principle for AIDS gene therapy. However, inefficient transfer of anti-HIV genes has limited success in AIDS gene therapy clinical trials. We previously developed foamy virus (FV) anti-HIV vectors that potently inhibit HIV replication and efficiently transduce human repopulating cells in a mouse xenotransplant model. Here we will develop improved combinatorial FV vectors designed to inhibit HIV escape and to be safer in preparation for using FV vectors in the clinic. Our proposal directly address two critical challenges for AIDS gene therapy, 1) to develop combinations of transgenes that potently inhibit HIV replication and escape, and 2) to improve the safety of HSC gene therapy and better understand safety in terms of potential clonal expansion and activation of proto-oncogenes. FV vectors offer several advantages for AIDS gene therapy including a distinct and potentially safer integration profile and the ability to efficiently deliver anti-HIV transgenes that interfere with HIV-based lentiviral vector titers. We will develop improved, safer FV anti-HIV vectors and directly compare their safety to lentiviral vectors which are currently being used in clinical trials. We will also explor ways to make FV vectors safer by modifying the integration profile to direct integration away from genes including proto-oncogenes. We will evaluate safety in vivo in human repopulating cells using an established xenograft model we have extensive experience with. Our proposal takes advantage of several unique properties of FV vectors and builds upon our published data showing FV vectors effectively deliver anti-HIV transgenes that interfere with HIV-based lentiviral vectors.

Public Health Relevance

The proposal will develop improved FV vectors for AIDS gene therapy and compare the safety of FV vectors to more commonly used lentiviral vectors. The proposed studies are expected to lead to a potent and safe FV vector for AIDS gene therapy that inhibits HIV escape and is suitable for clinical use.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI102672-02
Application #
8620606
Study Section
AIDS Discovery and Development of Therapeutics Study Section (ADDT)
Program Officer
Voulgaropoulou, Frosso
Project Start
2013-02-15
Project End
2018-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Washington State University
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
City
Pullman
State
WA
Country
United States
Zip Code
99164
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Everson, Elizabeth M; Trobridge, Grant D (2016) Retroviral vector interactions with hematopoietic cells. Curr Opin Virol 21:41-46
Adair, Jennifer E; Waters, Timothy; Haworth, Kevin G et al. (2016) Semi-automated closed system manufacturing of lentivirus gene-modified haematopoietic stem cells for gene therapy. Nat Commun 7:13173
Browning, Diana L; Trobridge, Grant D (2016) Insulators to Improve the Safety of Retroviral Vectors for HIV Gene Therapy. Biomedicines 4:
Browning, Diana L; Collins, Casey P; Hocum, Jonah D et al. (2016) Insulated Foamy Viral Vectors. Hum Gene Ther 27:255-66
Bii, Victor M; Trobridge, Grant D (2016) Identifying Cancer Driver Genes Using Replication-Incompetent Retroviral Vectors. Cancers (Basel) 8:
Nalla, Arun K; Williams, Theodore F; Collins, Casey P et al. (2016) Lentiviral vector-mediated insertional mutagenesis screen identifies genes that influence androgen independent prostate cancer progression and predict clinical outcome. Mol Carcinog 55:1761-1771
Humbert, Olivier; Gisch, Don W; Wohlfahrt, Martin E et al. (2016) Development of Third-generation Cocal Envelope Producer Cell Lines for Robust Lentiviral Gene Transfer into Hematopoietic Stem Cells and T-cells. Mol Ther 24:1237-46
Everson, Elizabeth M; Olzsko, Miles E; Leap, David J et al. (2016) A comparison of foamy and lentiviral vector genotoxicity in SCID-repopulating cells shows foamy vectors are less prone to clonal dominance. Mol Ther Methods Clin Dev 3:16048

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