Abstract:
:Diabetic retinopathy (DR) is the leading cause of blindness in the working-age population in the U.S. The vision-threatening processes of neuroglial and vascular dysfunction in DR occur in concert, driven by hyperglycemia and propelled by a pathway of inflammation, ischemia, vasodegeneration, and breakdown of the blood retinal barrier. Currently, no therapies exist for normalizing the vasculature in DR. Here, we show that a single intravitreal dose of adeno-associated virus serotype 2 encoding a more stable, soluble, and potent form of angiopoietin 1 (AAV2.COMP-Ang1) can ameliorate the structural and functional hallmarks of DR in Ins2Akita mice, with sustained effects observed through six months. In early DR, AAV2.COMP-Ang1 restored leukocyte-endothelial interaction, retinal oxygenation, vascular density, vascular marker expression, vessel permeability, retinal thickness, inner retinal cellularity, and retinal neurophysiological response to levels comparable with nondiabetic controls. In late DR, AAV2.COMP-Ang1 enhanced the therapeutic benefit of intravitreally delivered endothelial colony-forming cells by promoting their integration into the vasculature and thereby stemming further visual decline. AAV2.COMP-Ang1 single-dose gene therapy can prevent neurovascular pathology, support vascular regeneration, and stabilize vision in DR.
journal_name
Diabetesjournal_title
Diabetesauthors
Cahoon JM,Rai RR,Carroll LS,Uehara H,Zhang X,O'Neil CL,Medina RJ,Das SK,Muddana SK,Olson PR,Nielson S,Walker K,Flood MM,Messenger WB,Archer BJ,Barabas P,Krizaj D,Gibson CC,Li DY,Koh GY,Gao G,Stitt AW,Ambati BKdoi
10.2337/db14-1030subject
Has Abstractpub_date
2015-12-01 00:00:00pages
4247-59issue
12eissn
0012-1797issn
1939-327Xpii
db14-1030journal_volume
64pub_type
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