Adeno-associated virus type-2 expression of pigmented epithelium-derived factor or Kringles 1-3 of angiostatin reduce retinal neovascularization.
Neovascular diseases of the retina include age-related macular degeneration and diabetic retinopathy, and together they comprise the leading causes of adult-onset blindness in developed countries. Current surgical, pharmaceutical, and laser therapies for age-related macular degeneration (AMD) rarely result in improved vision, do not significantly prevent neovascularization (NV), and often result in at least some vision loss. To address this therapeutic gap, we determined the efficacy of recombinant adeno-associated viral (rAAV) serotype-2-mediated expression of pigment epithelium-derived factor (PEDF) or Kringle domains 1-3 of angiostatin (K1K3) in reducing aberrant vessel formation in a mouse model of ischemia-induced retinal NV. Both PEDF and K1K3 are potent inhibitors of NV when injected directly, hence expression of these therapeutic factors from rAAV may provide long-term protection from neovascular eye disease. rAAV vectors expressing the therapeutic gene were injected into one eye of postnatal day 0 (P0) newborn mouse pups. Retinal NV was induced in P7 mice by exposure to elevated oxygen for 5 days followed by room air for another five days. Retinal NV was quantified by the number of vascular-endothelial-cell nuclei above the inner-limiting membrane in P17 eyes. The number of such vascular endothelial cell nuclei in eyes treated with rAAV-PEDF or rAAV-K1K3 was significantly reduced (both P < 0.0000002) compared with control eyes. Ocular protein levels detected by ELISA correlate well with the reduction in NV and confirm that expression of antineovascular agents from rAAV vectors may be a therapeutically useful treatment of retinal or choroidal neovascular disease.
Raisler
Brian J
BJ
Department of Ophthalmology, Box 100284, University of Florida, Gainesville, FL 32610-0284, USA.
Berns
Kenneth I
KI
Grant
Maria B
MB
Beliaev
Denis
D
Hauswirth
William W
WW
D043168:Angiostatins; D000818:Animals; D000229:Dependovirus / Q000235:genetics*; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005136:Eye Proteins; D005822:Genetic Vectors; D018082:Kringles / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic / Q000235:genetics*; D009414:Nerve Growth Factors; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics*; D010958:Plasminogen / Q000737:chemistry / Q000235:genetics*; D011506:Proteins / Q000235:genetics*; D012171:Retinal Vessels / Q000254:growth & development*; D015843:Serpins / Q000235:genetics*; D000099174:Pigment Epithelium-Derived Factor
D043168:Angiostatins; D005136:Eye Proteins; D009414:Nerve Growth Factors; D010446:Peptide Fragments; D010958:Plasminogen; D011506:Proteins; D015843:Serpins; D000099174:Pigment Epithelium-Derived Factor