Marked inhibition of retinal neovascularization in rats following soluble-flt-1 gene transfer

Rossella Rota, Teresa Riccioni, Marco Zaccarini, Stefania Lamartina, Anna Del Gallo, Angelo Fusco, Imre Kovesdi, Emilio Balestrazzi, Damiano C. Abeni, Robin R. Ali, Maurizio C. Capogrossi

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Abstract

Background. In mouse models of retinopathy of prematurity (ROP) inhibitors of vascular endothelial growth factor (VEGF) functions administered systemically completely block retinal neovascularization. In contrast, selective ocular VEGF depletion has achieved an approx. 50% inhibition of retinal neovascular growth. It is unclear whether a more complete inhibition of new blood vessel development can be obtained with an anti-VEGF therapy localized to the eye. Therefore, the objective of the present study was to determine the effect of local anti-VEGF therapy in a different animal model which closely mimics human ROP. Methods. Rats were exposed to alternating cycles of high and low levels of oxygen for 14 days immediately after birth; thereafter, they were intravitreally injected with an adenoviral vector expressing a secreted form of the VEGF receptor flt-1 (Ad.sflt), which acts by sequestering VEGF. Contralateral eyes were injected with the control vector carrying the reporter gene expressing β-galactosidase (Ad.βGal). Results. At the peak of retinal neovascular growth, i.e. post-natal day 21 (P21), we observed up to 97.5% decrease in retinal neovascularization in animals injected with Ad.sflt. At the end of observation (P28), no significant difference in retinal vessel number was detected in both oxygen-injured and normoxic Ad.sflt-treated retinas compared with untreated or Ad.βGal-treated retinas. Conclusion. Adenoviral-mediated sflt-1 gene transfer induces a near-complete inhibition of ischemia-induced retinal neovascularization in rats without affecting pre-existing retinal vessels.

Original languageEnglish
Pages (from-to)992-1002
Number of pages11
JournalJournal of Gene Medicine
Volume6
Issue number9
DOIs
Publication statusPublished - Sep 2004

Fingerprint

Retinal Neovascularization
Vascular Endothelial Growth Factor A
Retinal Vessels
Retinopathy of Prematurity
Genes
Retina
Galactosidases
Oxygen
Vascular Endothelial Growth Factor Receptor-1
Growth
Reporter Genes
Blood Vessels
Ischemia
Animal Models
Observation
Parturition
Therapeutics

Keywords

  • Adenoviral vector
  • Gene therapy
  • Retinal neovascularization
  • Vascular endothelial growth factor

ASJC Scopus subject areas

  • Genetics

Cite this

Rota, R., Riccioni, T., Zaccarini, M., Lamartina, S., Del Gallo, A., Fusco, A., ... Capogrossi, M. C. (2004). Marked inhibition of retinal neovascularization in rats following soluble-flt-1 gene transfer. Journal of Gene Medicine, 6(9), 992-1002. https://doi.org/10.1002/jgm.586

Marked inhibition of retinal neovascularization in rats following soluble-flt-1 gene transfer. / Rota, Rossella; Riccioni, Teresa; Zaccarini, Marco; Lamartina, Stefania; Del Gallo, Anna; Fusco, Angelo; Kovesdi, Imre; Balestrazzi, Emilio; Abeni, Damiano C.; Ali, Robin R.; Capogrossi, Maurizio C.

In: Journal of Gene Medicine, Vol. 6, No. 9, 09.2004, p. 992-1002.

Research output: Contribution to journalArticle

Rota, R, Riccioni, T, Zaccarini, M, Lamartina, S, Del Gallo, A, Fusco, A, Kovesdi, I, Balestrazzi, E, Abeni, DC, Ali, RR & Capogrossi, MC 2004, 'Marked inhibition of retinal neovascularization in rats following soluble-flt-1 gene transfer', Journal of Gene Medicine, vol. 6, no. 9, pp. 992-1002. https://doi.org/10.1002/jgm.586
Rota, Rossella ; Riccioni, Teresa ; Zaccarini, Marco ; Lamartina, Stefania ; Del Gallo, Anna ; Fusco, Angelo ; Kovesdi, Imre ; Balestrazzi, Emilio ; Abeni, Damiano C. ; Ali, Robin R. ; Capogrossi, Maurizio C. / Marked inhibition of retinal neovascularization in rats following soluble-flt-1 gene transfer. In: Journal of Gene Medicine. 2004 ; Vol. 6, No. 9. pp. 992-1002.
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abstract = "Background. In mouse models of retinopathy of prematurity (ROP) inhibitors of vascular endothelial growth factor (VEGF) functions administered systemically completely block retinal neovascularization. In contrast, selective ocular VEGF depletion has achieved an approx. 50{\%} inhibition of retinal neovascular growth. It is unclear whether a more complete inhibition of new blood vessel development can be obtained with an anti-VEGF therapy localized to the eye. Therefore, the objective of the present study was to determine the effect of local anti-VEGF therapy in a different animal model which closely mimics human ROP. Methods. Rats were exposed to alternating cycles of high and low levels of oxygen for 14 days immediately after birth; thereafter, they were intravitreally injected with an adenoviral vector expressing a secreted form of the VEGF receptor flt-1 (Ad.sflt), which acts by sequestering VEGF. Contralateral eyes were injected with the control vector carrying the reporter gene expressing β-galactosidase (Ad.βGal). Results. At the peak of retinal neovascular growth, i.e. post-natal day 21 (P21), we observed up to 97.5{\%} decrease in retinal neovascularization in animals injected with Ad.sflt. At the end of observation (P28), no significant difference in retinal vessel number was detected in both oxygen-injured and normoxic Ad.sflt-treated retinas compared with untreated or Ad.βGal-treated retinas. Conclusion. Adenoviral-mediated sflt-1 gene transfer induces a near-complete inhibition of ischemia-induced retinal neovascularization in rats without affecting pre-existing retinal vessels.",
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AU - Del Gallo, Anna

AU - Fusco, Angelo

AU - Kovesdi, Imre

AU - Balestrazzi, Emilio

AU - Abeni, Damiano C.

AU - Ali, Robin R.

AU - Capogrossi, Maurizio C.

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N2 - Background. In mouse models of retinopathy of prematurity (ROP) inhibitors of vascular endothelial growth factor (VEGF) functions administered systemically completely block retinal neovascularization. In contrast, selective ocular VEGF depletion has achieved an approx. 50% inhibition of retinal neovascular growth. It is unclear whether a more complete inhibition of new blood vessel development can be obtained with an anti-VEGF therapy localized to the eye. Therefore, the objective of the present study was to determine the effect of local anti-VEGF therapy in a different animal model which closely mimics human ROP. Methods. Rats were exposed to alternating cycles of high and low levels of oxygen for 14 days immediately after birth; thereafter, they were intravitreally injected with an adenoviral vector expressing a secreted form of the VEGF receptor flt-1 (Ad.sflt), which acts by sequestering VEGF. Contralateral eyes were injected with the control vector carrying the reporter gene expressing β-galactosidase (Ad.βGal). Results. At the peak of retinal neovascular growth, i.e. post-natal day 21 (P21), we observed up to 97.5% decrease in retinal neovascularization in animals injected with Ad.sflt. At the end of observation (P28), no significant difference in retinal vessel number was detected in both oxygen-injured and normoxic Ad.sflt-treated retinas compared with untreated or Ad.βGal-treated retinas. Conclusion. Adenoviral-mediated sflt-1 gene transfer induces a near-complete inhibition of ischemia-induced retinal neovascularization in rats without affecting pre-existing retinal vessels.

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