Intravitreal AAV2.COMP-Ang1 Prevents Neurovascular Degeneration in a Murine Model of Diabetic Retinopathy

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.

Diabetic Retinopathy: Battling the Global Epidemic

“…In late DR, AAV2.COMP-Ang1 enhanced the therapeutic benefit of intravitreally delivered endothelial colony-forming cells, a key vascular-derived progenitor population, by promoting their integration into the vasculature. 24 This puts forth the idea of gene therapy for DR and that AAV2.COMP-Ang1 single dose could be considered in the future as a targeted therapy to prevent neurovascular pathology, support vascular regeneration, and even stabilize vision in DR.…”

Angiopoietin-1 and Angiopoietin-2 in metabolic disorders: therapeutic strategies to restore the highs and lows of angiogenesis in diabetes

“…Intriguingly, Ang2 overexpression in the retina or its intravitreal injection in rodent models enhances vascular impairment, suggesting that it plays a role in diabetic vasoregression by destabilizing pericytes, inducing similar damages to those observed in early diabetic retinopathy [87,88]. Conversely, intraocular injection of Ang1 suppressed retinal edema in diabetic mice [89]. This delivery method is also attractive because it reduces the generalized side effects seen with systemic administration.…”

“…High Ang1 levels might act synergistically with elevated VEGF in the diabetic retina to induce angiogenic changes [27]. It was recently demonstrated that adeno-associated virus serotype 2 encoding a more stable, soluble and potent form of Ang1 (AAV2.COMP-Ang1) can improve the structural and functional hallmarks of diabetic retinopathy in Ins2Akita mice [89].…”

Future opportunities in diabetic retinopathy research

“…The advent of intraocular drug delivery of steroids and anti-vascular endothelial growth factor (VEGF) inhibitors over the past decade has established the principle of direct pharmacotherapy for diabetic retinopathy. Additional pathways, including plasma kallikrein signaling 38 , loss of neurotrophic support 39, 40 , and deficient angiopoietin 1 signaling 41 may be targets for future therapy. Direct ocular drug administration will continue to be a major route of diabetic retinopathy treatment with sustained delivery methods now in clinical testing 42 .…”