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https://hdl.handle.net/2440/41981
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Type: | Journal article |
Title: | G-CSF-lentivirus administration in rats provided sustained elevated neutrophil counts and subsequent EPO-lentivirus administration increased hematocrits |
Author: | Brzezinski, M. Yanay, O. Waldron, L. Barry, S. Osborne, W. |
Citation: | Journal of Gene Medicine, 2007; 9(7):571-578 |
Publisher: | John Wiley & Sons Ltd |
Issue Date: | 2007 |
ISSN: | 1099-498X 1521-2254 |
Statement of Responsibility: | Margaret Brzezinski, Ofer Yanay, Lanaya Waldron, Simon C. Barry, William R. A. Osborne |
Abstract: | <h4>Background</h4>Towards gene therapy treatment of patients with neutropenia, characterized by neutrophil counts < 500 cells/microl, we investigated the ability of lentivirus vectors to provide sustained granulocyte colony-stimulating factor (G-CSF) delivery and to permit transgene expression from a second virus administration in a preclinical rat model.<h4>Methods</h4>Rats were injected intramuscularly (IM) with 24 x 10(6) and 9 x 10(6) infectious units (IU) of a VSV-G-pseudotyped self-inactivating (SIN) lentivirus encoding rat G-CSF cDNA and containing cPPT and PRE elements. To determine the effectiveness of a second virus administration treated rats and a naïve rat received erythropoietin (EPO)-lentivirus IM. Rats were monitored for neutrophil and red blood cell production. Lentivirus antibodies were assayed by virus-neutralizing assay and ELISA.<h4>Results</h4>High and low dose virus administration increased neutrophil counts to 5660 +/- 930 cells/microl (mean +/- SD) and 4010 +/- 850 cells/microl, respectively, that were sustained for > 17 months and were significantly higher than controls counts of 1890 +/- 570 cells/microl (p< or =0.0002). Rats treated with EPO-virus produced significantly increased hematocrits (HCT) (63.1 +/- 4.3% vs. 46.0 +/- 3.2%, p < 0.0001) without effect on G-CSF-virus-mediated neutrophil production. Antivirus antibodies were not detectable at serum dilutions > or =1:10 by virus neutralization or ELISA. Lymphocytes and platelets were not significantly different between control and treated animals (p > 0.1). Only genomic DNA from muscle at injection sites was positive for provirus suggesting lack of virus spread.<h4>Conclusions</h4>G-CSF-lentivirus administered IM provided elevated, sustained neutrophil counts that were unchanged by subsequent EPO-lentivirus administration. Significantly increased hematocrits were obtained following EPO-lentivirus delivery. These data support the treatment of patients with severe chronic neutropenia by dosed lentivirus delivery IM. |
Keywords: | Neutrophils Hela Cells Animals Rats, Inbred F344 Humans Rats Proviruses Lentivirus Erythropoietin Granulocyte Colony-Stimulating Factor DNA Antibodies, Viral Blood Cell Count Hematocrit Genome Male Genetic Therapy |
DOI: | 10.1002/jgm.1050 |
Published version: | http://dx.doi.org/10.1002/jgm.1050 |
Appears in Collections: | Aurora harvest Paediatrics publications |
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