Helper-dependent adenovirus for the gene therapy of proliferative retinopathies

Stable gene transfer, regulated gene expression and therapeutic efficacy

Stefania Lamartina, Monica Cimino, Giuseppe Roscilli, Ernesta Dammassa, Domenico Lazzaro, Rossella Rota, Gennaro Ciliberto, Carlo Toniatti

Research output: Contribution to journalArticle

42 Citations (Scopus)

Abstract

Background: Ocular neovascular disorders, such as diabetic retinopathy and age-related macular degeneration, are the principal causes of blindness in developed countries. Current treatments are of limited efficacy, whereas a therapy based on intraocular gene transfer of angiostatic factors represents a promising alternative. For the first time we have explored the potential of helper-dependent adenovirus (HD-Ad), the last generation of Ad vectors, in the therapy of retinal neovascularization. Methods: We first analyzed efficiency and stability of intraretinal gene transfer following intravitreous injection in mice. A HD-Ad vector expressing green fluorescent protein (GFP) under the control of the cytomegalovirus (CMV) promoter (HD-Ad/GFP) was compared with a first-generation (E1/E3-deleted) Ad vector carrying an identical GFP expression cassette (FG-Ad/GFP). We also constructed HD-Ad vectors expressing a soluble form of the VEGF receptor (sFlt-1) in a constitutive (HD-Ad/sFlt-1) or doxycycline (dox)-inducible (HD-Ad/S-M2/ sFlt-1) manner and tested their therapeutic efficacy upon intravitreous delivery in a rat model of oxygen-induced retinopathy (OIR). Results: HD-Ad/GFP promoted long-lasting (up to 1 year) transgene expression in retinal Müller cells, in marked contrast with the short-term expression observed with FG-Ad/GFP. Intravitreous injection of HD-Ad vectors expressing sFlt-1 resulted in detectable levels of sFlt-1 and inhibited retinal neovascularization by more than 60% in a rat model of OIR. Notably, the therapeutic efficacy of the inducible vector HD-Ad/S-M2/sFlt-1 was strictly dox-dependent. Conclusions: HD-Ad vectors enable stable gene transfer and regulated expression of angiostatic factors following intravitreous injection and thus are attractive vehicles for the gene therapy of neovascular diseases of the retina.

Original languageEnglish
Pages (from-to)862-874
Number of pages13
JournalJournal of Gene Medicine
Volume9
Issue number10
DOIs
Publication statusPublished - Oct 2007

Fingerprint

Adenoviridae
Genetic Therapy
Gene Expression
Green Fluorescent Proteins
Genes
Retinal Neovascularization
Therapeutics
Doxycycline
Injections
Oxygen
Transfer Factor
Vascular Endothelial Growth Factor Receptor
Macular Degeneration
Diabetic Retinopathy
Blindness
Cytomegalovirus
Transgenes
Developed Countries
Retina

Keywords

  • Helper-dependent Adenovirus
  • Retinopathy
  • sFlt-1
  • Transcriptional regulation

ASJC Scopus subject areas

  • Genetics

Cite this

Helper-dependent adenovirus for the gene therapy of proliferative retinopathies : Stable gene transfer, regulated gene expression and therapeutic efficacy. / Lamartina, Stefania; Cimino, Monica; Roscilli, Giuseppe; Dammassa, Ernesta; Lazzaro, Domenico; Rota, Rossella; Ciliberto, Gennaro; Toniatti, Carlo.

In: Journal of Gene Medicine, Vol. 9, No. 10, 10.2007, p. 862-874.

Research output: Contribution to journalArticle

Lamartina, Stefania ; Cimino, Monica ; Roscilli, Giuseppe ; Dammassa, Ernesta ; Lazzaro, Domenico ; Rota, Rossella ; Ciliberto, Gennaro ; Toniatti, Carlo. / Helper-dependent adenovirus for the gene therapy of proliferative retinopathies : Stable gene transfer, regulated gene expression and therapeutic efficacy. In: Journal of Gene Medicine. 2007 ; Vol. 9, No. 10. pp. 862-874.
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AU - Dammassa, Ernesta

AU - Lazzaro, Domenico

AU - Rota, Rossella

AU - Ciliberto, Gennaro

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