Specific organ gene transfer in vivo by regional organ perfusion with herpes viral amplicon vectors: Implications for local gene therapy

Ari D. Brooks, Bruce Ng, David Liu, Michael Brownlee, Michael Burt, Howard J. Federoff, Yuman Fong

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Background. Many gene therapy strategies would benefit from efficient, regional organ delivery of therapeutic genes. Methods. Regional perfusions of lung, liver, or bladder were performed to determine if rapid and efficient gene transfer can be accomplished in vivo, and to determine if in vivo gene transfer can be limited to the organ of interest. In addition, herpes simplex virus tumor necrosis factor (HSVtnf), carrying the human tumor necrosis factor α gene was used as a treatment for methylcholanthrene sarcoma in a syngeneic lung metastases model in Fisher rats. Results. A 20-minute perfusion using HSV carrying β-galactosidase (HSVlac) produced significant expression of this marker gene isolated to the target organs, without organ-specific tissue injury or inflammation. Regional perfusion of organs with HSV carrying the cytokine gene tumor necrosis factor α also resulted in high-level local organ production of this cytokine (2851 ± 53 pg/g tissue in perfused lung versus 0 for the contralateral lung). For the current vector construct, expression of the gene of interest peaked between 2 and 4 days and was undetectable by 2 weeks after perfusion. In animals undergoing perfusion as treatment for pulmonary sarcoma, there was no difference between tumor counts in lungs perfused with HSVlac (17 ± 6) or HSVtnf (22 ± 8), but either treatment resulted in lower tumor counts than controls (111 ± 24 nodules per lung, P <02). Conclusions. Regional organ perfusion using herpes viral vectors is an effective and well-tolerated in vivo method of transiently delivering potentially toxic gene products to target organs in directing gene therapy. Regional lung perfusion with HSV amplicons reduces tumor burden in a rat model of pulmonary metastases, though HSVtnf cannot be demonstrated to augment the cytopathic effect of the HSV amplicon alone in the current model.

Original languageEnglish (US)
Pages (from-to)324-334
Number of pages11
JournalSurgery
Volume129
Issue number3
DOIs
StatePublished - 2001

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Genetic Therapy
Perfusion
Lung
Genes
Simplexvirus
Tumor Necrosis Factor-alpha
Sarcoma
Galactosidases
Cytokines
Neoplasm Metastasis
Gene Expression
Methylcholanthrene
Poisons
Therapeutics
Tumor Burden
Neoplasms
Urinary Bladder
Inflammation
Liver
Wounds and Injuries

ASJC Scopus subject areas

  • Surgery

Cite this

Specific organ gene transfer in vivo by regional organ perfusion with herpes viral amplicon vectors : Implications for local gene therapy. / Brooks, Ari D.; Ng, Bruce; Liu, David; Brownlee, Michael; Burt, Michael; Federoff, Howard J.; Fong, Yuman.

In: Surgery, Vol. 129, No. 3, 2001, p. 324-334.

Research output: Contribution to journalArticle

Brooks, Ari D. ; Ng, Bruce ; Liu, David ; Brownlee, Michael ; Burt, Michael ; Federoff, Howard J. ; Fong, Yuman. / Specific organ gene transfer in vivo by regional organ perfusion with herpes viral amplicon vectors : Implications for local gene therapy. In: Surgery. 2001 ; Vol. 129, No. 3. pp. 324-334.
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N2 - Background. Many gene therapy strategies would benefit from efficient, regional organ delivery of therapeutic genes. Methods. Regional perfusions of lung, liver, or bladder were performed to determine if rapid and efficient gene transfer can be accomplished in vivo, and to determine if in vivo gene transfer can be limited to the organ of interest. In addition, herpes simplex virus tumor necrosis factor (HSVtnf), carrying the human tumor necrosis factor α gene was used as a treatment for methylcholanthrene sarcoma in a syngeneic lung metastases model in Fisher rats. Results. A 20-minute perfusion using HSV carrying β-galactosidase (HSVlac) produced significant expression of this marker gene isolated to the target organs, without organ-specific tissue injury or inflammation. Regional perfusion of organs with HSV carrying the cytokine gene tumor necrosis factor α also resulted in high-level local organ production of this cytokine (2851 ± 53 pg/g tissue in perfused lung versus 0 for the contralateral lung). For the current vector construct, expression of the gene of interest peaked between 2 and 4 days and was undetectable by 2 weeks after perfusion. In animals undergoing perfusion as treatment for pulmonary sarcoma, there was no difference between tumor counts in lungs perfused with HSVlac (17 ± 6) or HSVtnf (22 ± 8), but either treatment resulted in lower tumor counts than controls (111 ± 24 nodules per lung, P <02). Conclusions. Regional organ perfusion using herpes viral vectors is an effective and well-tolerated in vivo method of transiently delivering potentially toxic gene products to target organs in directing gene therapy. Regional lung perfusion with HSV amplicons reduces tumor burden in a rat model of pulmonary metastases, though HSVtnf cannot be demonstrated to augment the cytopathic effect of the HSV amplicon alone in the current model.

AB - Background. Many gene therapy strategies would benefit from efficient, regional organ delivery of therapeutic genes. Methods. Regional perfusions of lung, liver, or bladder were performed to determine if rapid and efficient gene transfer can be accomplished in vivo, and to determine if in vivo gene transfer can be limited to the organ of interest. In addition, herpes simplex virus tumor necrosis factor (HSVtnf), carrying the human tumor necrosis factor α gene was used as a treatment for methylcholanthrene sarcoma in a syngeneic lung metastases model in Fisher rats. Results. A 20-minute perfusion using HSV carrying β-galactosidase (HSVlac) produced significant expression of this marker gene isolated to the target organs, without organ-specific tissue injury or inflammation. Regional perfusion of organs with HSV carrying the cytokine gene tumor necrosis factor α also resulted in high-level local organ production of this cytokine (2851 ± 53 pg/g tissue in perfused lung versus 0 for the contralateral lung). For the current vector construct, expression of the gene of interest peaked between 2 and 4 days and was undetectable by 2 weeks after perfusion. In animals undergoing perfusion as treatment for pulmonary sarcoma, there was no difference between tumor counts in lungs perfused with HSVlac (17 ± 6) or HSVtnf (22 ± 8), but either treatment resulted in lower tumor counts than controls (111 ± 24 nodules per lung, P <02). Conclusions. Regional organ perfusion using herpes viral vectors is an effective and well-tolerated in vivo method of transiently delivering potentially toxic gene products to target organs in directing gene therapy. Regional lung perfusion with HSV amplicons reduces tumor burden in a rat model of pulmonary metastases, though HSVtnf cannot be demonstrated to augment the cytopathic effect of the HSV amplicon alone in the current model.

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