Intravitreal AAV2.COMP-Ang1 prevents neurovascular degeneration in a murine model of diabetic retinopathy

Judd M Cahoon, Ruju R Rai, Lara S Carroll, Hironori Uehara, Xiaohui Zhang, Christina L O'Neil, Reinhold J Medina, Subtrata K Das, Santosh K Muddana, Paul R Olson, Spencer Nielson, Kortnie Walker, Maggie M Flood, Wyatt B Messenger, Bonnie J Archer, Peter Barabas, David Krizaj, Christopher C Gibson, Dean Y Li, Gou Y KohGuangping Gao, Alan W Stitt, Balamurali K Ambati

Research output: Contribution to journalArticlepeer-review

29 Citations (Scopus)

Abstract

Diabetic retinopathy (DR) is the leading cause of blindness in the working-age population in the United States. 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 to non-diabetic 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.
Original languageEnglish
Pages (from-to)4247-4259
Number of pages12
JournalDiabetes
Volume64
Issue number12
Early online date04 Sep 2015
DOIs
Publication statusPublished - 01 Dec 2015

Bibliographical note

© 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

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