Long-term evaluation of AAV-mediated sFlt-1 gene therapy for ocular neovascularization in mice and monkeys

Chooi May Lai, Wei Yong Shen, Meliha Brankov, Yvonne K.Y. Lai, Nigel L. Barnett, Shu Yen Lee, Ian Y.S. Yeo, Ranjana Mathur, Joseph E.S. Ho, Paul Pineda, Amutha Barathi, Chong Lye Ang, Ian J. Constable, Elizabeth P. Rakoczy

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Abstract

Vascular endothelial growth factor (VEGF) is one of the major mediators of retinal ischemia-associated neovascularization. We have shown here that adeno-associated virus (AAV)-mediated expression of sFlt-1, a soluble form of the Flt-1 VEGF receptor, was maintained for up to 8 and 17 months postinjection in mice and in monkeys, respectively. The expression of sFlt-1 was associated with the long-term (8 months) regression of neovascular vessels in 85% of trVEGF029 eyes. In addition, it resulted in the maintenance of retinal morphology, as the majority of the treated trVEGF029 eyes (75%) retained high numbers of photoreceptors, and in retinal function as measured by electroretinography. AAV-mediated expression of sFlt-1 prevented the development of laser photocoagulation-induced choroidal neovascularization in all treated monkey eyes. There were no clinically or histologically detectable signs of toxicity present in either animal model following AAV.sFlt injection. These results suggest that AAV-mediated secretion gene therapy could be considered for treatment of retinal and choroidal neovascularizations.

Original languageEnglish
Pages (from-to)659-668
Number of pages10
JournalMolecular Therapy
Volume12
Issue number4
DOIs
Publication statusPublished - 1 Oct 2005
Externally publishedYes

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Dependovirus
Genetic Therapy
Haplorhini
Choroidal Neovascularization
Retinal Neovascularization
Vascular Endothelial Growth Factor Receptor-1
Electroretinography
Vertebrate Photoreceptor Cells
Light Coagulation
Vascular Endothelial Growth Factor A
Lasers
Ischemia
Animal Models
Maintenance
Injections
Therapeutics

Cite this

Lai, Chooi May ; Shen, Wei Yong ; Brankov, Meliha ; Lai, Yvonne K.Y. ; Barnett, Nigel L. ; Lee, Shu Yen ; Yeo, Ian Y.S. ; Mathur, Ranjana ; Ho, Joseph E.S. ; Pineda, Paul ; Barathi, Amutha ; Ang, Chong Lye ; Constable, Ian J. ; Rakoczy, Elizabeth P. / Long-term evaluation of AAV-mediated sFlt-1 gene therapy for ocular neovascularization in mice and monkeys. In: Molecular Therapy. 2005 ; Vol. 12, No. 4. pp. 659-668.
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abstract = "Vascular endothelial growth factor (VEGF) is one of the major mediators of retinal ischemia-associated neovascularization. We have shown here that adeno-associated virus (AAV)-mediated expression of sFlt-1, a soluble form of the Flt-1 VEGF receptor, was maintained for up to 8 and 17 months postinjection in mice and in monkeys, respectively. The expression of sFlt-1 was associated with the long-term (8 months) regression of neovascular vessels in 85{\%} of trVEGF029 eyes. In addition, it resulted in the maintenance of retinal morphology, as the majority of the treated trVEGF029 eyes (75{\%}) retained high numbers of photoreceptors, and in retinal function as measured by electroretinography. AAV-mediated expression of sFlt-1 prevented the development of laser photocoagulation-induced choroidal neovascularization in all treated monkey eyes. There were no clinically or histologically detectable signs of toxicity present in either animal model following AAV.sFlt injection. These results suggest that AAV-mediated secretion gene therapy could be considered for treatment of retinal and choroidal neovascularizations.",
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Lai, CM, Shen, WY, Brankov, M, Lai, YKY, Barnett, NL, Lee, SY, Yeo, IYS, Mathur, R, Ho, JES, Pineda, P, Barathi, A, Ang, CL, Constable, IJ & Rakoczy, EP 2005, 'Long-term evaluation of AAV-mediated sFlt-1 gene therapy for ocular neovascularization in mice and monkeys' Molecular Therapy, vol. 12, no. 4, pp. 659-668. https://doi.org/10.1016/j.ymthe.2005.04.022

Long-term evaluation of AAV-mediated sFlt-1 gene therapy for ocular neovascularization in mice and monkeys. / Lai, Chooi May; Shen, Wei Yong; Brankov, Meliha; Lai, Yvonne K.Y.; Barnett, Nigel L.; Lee, Shu Yen; Yeo, Ian Y.S.; Mathur, Ranjana; Ho, Joseph E.S.; Pineda, Paul; Barathi, Amutha; Ang, Chong Lye; Constable, Ian J.; Rakoczy, Elizabeth P.

In: Molecular Therapy, Vol. 12, No. 4, 01.10.2005, p. 659-668.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Lai, Yvonne K.Y.

AU - Barnett, Nigel L.

AU - Lee, Shu Yen

AU - Yeo, Ian Y.S.

AU - Mathur, Ranjana

AU - Ho, Joseph E.S.

AU - Pineda, Paul

AU - Barathi, Amutha

AU - Ang, Chong Lye

AU - Constable, Ian J.

AU - Rakoczy, Elizabeth P.

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N2 - Vascular endothelial growth factor (VEGF) is one of the major mediators of retinal ischemia-associated neovascularization. We have shown here that adeno-associated virus (AAV)-mediated expression of sFlt-1, a soluble form of the Flt-1 VEGF receptor, was maintained for up to 8 and 17 months postinjection in mice and in monkeys, respectively. The expression of sFlt-1 was associated with the long-term (8 months) regression of neovascular vessels in 85% of trVEGF029 eyes. In addition, it resulted in the maintenance of retinal morphology, as the majority of the treated trVEGF029 eyes (75%) retained high numbers of photoreceptors, and in retinal function as measured by electroretinography. AAV-mediated expression of sFlt-1 prevented the development of laser photocoagulation-induced choroidal neovascularization in all treated monkey eyes. There were no clinically or histologically detectable signs of toxicity present in either animal model following AAV.sFlt injection. These results suggest that AAV-mediated secretion gene therapy could be considered for treatment of retinal and choroidal neovascularizations.

AB - Vascular endothelial growth factor (VEGF) is one of the major mediators of retinal ischemia-associated neovascularization. We have shown here that adeno-associated virus (AAV)-mediated expression of sFlt-1, a soluble form of the Flt-1 VEGF receptor, was maintained for up to 8 and 17 months postinjection in mice and in monkeys, respectively. The expression of sFlt-1 was associated with the long-term (8 months) regression of neovascular vessels in 85% of trVEGF029 eyes. In addition, it resulted in the maintenance of retinal morphology, as the majority of the treated trVEGF029 eyes (75%) retained high numbers of photoreceptors, and in retinal function as measured by electroretinography. AAV-mediated expression of sFlt-1 prevented the development of laser photocoagulation-induced choroidal neovascularization in all treated monkey eyes. There were no clinically or histologically detectable signs of toxicity present in either animal model following AAV.sFlt injection. These results suggest that AAV-mediated secretion gene therapy could be considered for treatment of retinal and choroidal neovascularizations.

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