EIAV vector-mediated delivery of endostatin or angiostatin inhibits angiogenesis and vascular hyperpermeability in experimental CNV.
We evaluated the efficacy of equine infectious anaemia virus (EIAV)-based lentiviral vectors encoding endostatin (EIAV.endostatin) or angiostatin (EIAV.angiostatin) in inhibiting angiogenesis and vascular hyperpermeability in the laser-induced model of choroidal neovascularisation (CNV). Equine infectious anaemia virus.endostatin, EIAV.angiostatin or control (EIAV.null) vectors were administered into the subretinal space of C57Bl/6J mice. Two weeks after laser injury CNV areas and the degree of vascular hyperpermeability were measured by image analysis of in vivo fluorescein angiograms. Compared with EIAV.null-injected eyes, EIAV.endostatin resulted in a 59.5% (P<0.001) reduction in CNV area and a reduction in hyperpermeability of 25.6% (P<0.05). Equine infectious anaemia virus.angiostatin resulted in a 50.0% (P<0.05) reduction in CNV area and a 23.9% (P<0.05) reduction in hyperpermeability. Equine infectious anaemia virus.endostatin, but not EIAV.angiostatin significantly augmented the frequency of apoptosis within the induced CNV as compared with injected controls. TdT-dUTP terminal nick end labeling analysis 5 weeks post-injection, and histological and retinal flatmount analysis 12 months post-injection revealed no evidence of vector- or transgene expression-related deleterious effects on neurosensory retinal cells, or mature retinal vasculature in non-lasered eyes. Highly expressing EIAV-based vectors encoding endostatin or angiostatin effectively control angiogenesis and hyperpermeability in experimental CNV without long-term deleterious effects, supporting the use of such a strategy in the management of patients with exudative age-related macular degeneration.
Balaggan
K S
KS
Division of Molecular Therapy, Institute of Ophthalmology, London, UK. kambalaggan@yahoo.co.uk
Binley
K
K
Esapa
M
M
MacLaren
R E
RE
Iqball
S
S
Duran
Y
Y
Pearson
R A
RA
Kan
O
O
Barker
S E
SE
Smith
A J
AJ
Bainbridge
J W B
JW
Naylor
S
S
Ali
R R
RR
D020533:Angiogenesis Inhibitors / Q000235:genetics; D043168:Angiostatins / Q000235:genetics*; D000818:Animals; D017209:Apoptosis; D002199:Capillary Permeability; D020256:Choroidal Neovascularization / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy*; D043169:Endostatins / Q000235:genetics*; D005451:Fluorescein Angiography; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage* / Q000235:genetics; D020287:In Situ Nick-End Labeling; D004860:Infectious Anemia Virus, Equine / Q000235:genetics*; D007834:Lasers; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D009389:Neovascularization, Pathologic; D014161:Transduction, Genetic / Q000379:methods; D015854:Up-Regulation
D020533:Angiogenesis Inhibitors; D043169:Endostatins; D043168:Angiostatins