Long-term Evaluation of AAV-Mediated sFlt-1 Gene Therapy for Ocular Neovascularization in Mice and Monkeys

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.

Novel anti-VEGF chimeric molecules delivered by AAV vectors for inhibition of retinal neovascularization

“…21 Subretinal delivery of AAV2 encoding full-length sFlt-1 gene has been successfully tested in mouse and in primate models of ocular neovascularization. 22,27,28 An adenoviral vector encoding full-length sFlt-1, injected both intravitreously or periocularly suppressed choroidal neovascularization at rupture sites in Bruch's membrane. 29 Our AAV2.sFLT01 vector administered intravitreally to neonatal mice significantly reduced the occurrence of neovascularization in the OIR model.…”

“…18 Adeno-associated virus (AAV) vectors offer an attractive tool for intraocular gene delivery because of their nonpathogenic nature, low toxicity, minimal immunogenicity and long-term persistence. [19][20][21][22] Intravitreal administration of AAV serotype 2 (AAV2) vector in mice results mostly in transduction of ganglion cells and few cells in the inner nuclear layer. 21 Subretinal delivery of AAV2 vector encoding full-length sFlt-1 (transduction of photoreceptors and retinal pigmented epithelium) prevented development of laser-induced choroidal neovascularization in all treated monkeys.…”

“…21 Subretinal delivery of AAV2 vector encoding full-length sFlt-1 (transduction of photoreceptors and retinal pigmented epithelium) prevented development of laser-induced choroidal neovascularization in all treated monkeys. 22 In this study we have designed and constructed small novel soluble hybrid molecules that have strong anti-VEGF activity in vitro, incorporated these molecules into AAV2 vectors and then tested in vivo persistence of expression and efficacy and safety following intravitreal delivery of these AAV2-based vectors in the oxygeninduced retinopathy of prematurity (OIR) mouse model.…”

Dégénérescence des photorécepteurs: stratégies thérapeutiques et nouvelles perspectives

“…On observe, chez ces animaux, une inhibition de la néovascularisation rétinienne par rapport à des animaux témoins. Cette approche a aussi été appliquée avec succès chez le primate en utilisant un vecteur codant sFlt-1 (Lai et al 2005 ;Lai et al 2009). …”

Seeing the light: New insights into the molecular pathogenesis of retinal diseases

“…Expression of pigment epithelium-derived factor (PEDF) has been shown to suppress ocular neovascularization in several models (Mori et al, 2001a(Mori et al, ,b, 2002Auricchio et al, 2002;Raisler et al, 2002;Gehlbach et al, 2003a) and a phase I trial in patients with neovascular AMD showed promise . Other promising transgenes for treatment of ocular neovascularization include endostatin, which reduces excessive vascular permeability in addition to suppressing neovascularization (Auricchio et al, 2002;Takahashi et al, 2003), angiostatin (Lai et al, 2001a;Raisler et al, 2002;Igarashi et al, 2003), and soluble VEGF receptor 1 (Honda et al, 2000;Lai et al, 2001bLai et al, , 2005Bainbridge et al, 2002;Gehlbach et al, 2003b;Rota et al, 2004).…”