In order to effectively correct genetic disorders in humans, safe and efficient gene delivery systems must be? developed, produced in large quantities, purified from contaminants, free of replication competent virus? (RCV) and concentrated to high titers. The engineering of effective gene transfer vectors has been a crucial? factor for the efficient delivery and expression of therapeutic gene products in vivo. Viruses have been? adapted for use as gene transfer vectors taking advantage of natural viral mechanisms designed to? efficiently and effectively deliver DMA to the host cell nucleus. Among these, herpes simplex virus type 1? (HSV-1) represents an excellent candidate vector for delivery to the peripheral (PNS) and central nervous? systems (CMS) based on the natural biology of the virus that includes the establishment of a life-long latent? state in neurons in which the viral genome persists as an episomal molecule. Considerable effort in the? development of HSV-1 vectors has resulted in the engineering of totally replication defective vectors that are? non-toxic for neurons and are capable of long-term transgene expression in neurons of the PNS. As well,? efforts in process development have resulted in scaleable systems capable of manufacturing these vectors? for pre-clinical efficacy and safety testing. The primary goal of the Pre-Clinical Vector Core will be to provide? large quantities of concentrated and purified HSV-1 vectors expressing single or multiple therapeutic genes? to each of the projects for the proposed experiments. The Pre-Clinical Vector Core will work with the? projects to provide optimal vector quantity and purity. The proposed design of the Pre-Clinical Vector Core? will be to provide the support necessary to successfully exploit the available technology.? The specific aims of the Pre-Clinical Vector Core are: (1) to provide each investigator with the appropriate? purified HSV-1 vector already in-hand expressing the required therapeutic or marker gene to successfully? complete the proposed pre-clinical experiments; and (2) to provide technical assistance, reagents, and? protocols to each of the projects including the development of new or modified protocols for the production? and purification of HSV vectors for pre-clinical experiments. Should success in these projects lead to the? initiation of Phase-l human clinical trials, the Pre-Clinical Vector Core is set up to transition the production of? these vectors to the Human Gene Therapy Applications Laboratory (HGTAL) as part of the University of? Pittsburgh Molecular Medicine Institute (MMI).

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Program Projects (P01)
Project #
5P01DK044935-12
Application #
7478754
Study Section
Special Emphasis Panel (ZDK1)
Project Start
Project End
Budget Start
2007-08-01
Budget End
2008-07-31
Support Year
12
Fiscal Year
2007
Total Cost
$280,455
Indirect Cost
Name
University of Pittsburgh
Department
Type
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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Verlengia, Gianluca; Miyagawa, Yoshitaka; Ingusci, Selene et al. (2017) Engineered HSV vector achieves safe long-term transgene expression in the central nervous system. Sci Rep 7:1507
Miyagawa, Yoshitaka; Verlengia, Gianluca; Reinhart, Bonnie et al. (2017) Deletion of the Virion Host Shut-off Gene Enhances Neuronal-Selective Transgene Expression from an HSV Vector Lacking Functional IE Genes. Mol Ther Methods Clin Dev 6:79-90
Laemmle, Lillian L; Cohen, Justus B; Glorioso, Joseph C (2016) Constitutive Expression of GATA4 Dramatically Increases the Cardiogenic Potential of D3 Mouse Embryonic Stem Cells. Open Biotechnol J 10:248-257
Goins, William F; Hall, Bonnie; Cohen, Justus B et al. (2016) Retargeting of herpes simplex virus (HSV) vectors. Curr Opin Virol 21:93-101
Reinhart, Bonnie; Goins, William F; Harel, Asaff et al. (2016) An HSV-based library screen identifies PP1? as a negative TRPV1 regulator with analgesic activity in models of pain. Mol Ther Methods Clin Dev 3:16040
Miyagawa, Yoshitaka; Marino, Pietro; Verlengia, Gianluca et al. (2015) Herpes simplex viral-vector design for efficient transduction of nonneuronal cells without cytotoxicity. Proc Natl Acad Sci U S A 112:E1632-41
Majima, Tsuyoshi; Funahashi, Yasuhito; Takai, Shun et al. (2015) Herpes Simplex Virus Vector-Mediated Gene Delivery of Poreless TRPV1 Channels Reduces Bladder Overactivity and Nociception in Rats. Hum Gene Ther 26:734-42
Sha, Huizi; Zou, Zhengyun; Xin, Kai et al. (2015) Tumor-penetrating peptide fused EGFR single-domain antibody enhances cancer drug penetration into 3D multicellular spheroids and facilitates effective gastric cancer therapy. J Control Release 200:188-200
Goins, William F; Huang, Shaohua; Cohen, Justus B et al. (2014) Engineering HSV-1 vectors for gene therapy. Methods Mol Biol 1144:63-79

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