1. Intravitreal AAV2.COMP-Ang1 Prevents Neurovascular Degeneration in a Murine Model of Diabetic Retinopathy
- Author
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Judd Cahoon, Dean Y. Li, David Krizaj, Bonnie Archer, Xiaohui Zhang, Subtrata K. Das, Christopher C. Gibson, Wyatt B. Messenger, Reinhold J. Medina, Paul R. Olson, Guangping Gao, Kortnie Walker, Ruju R. Rai, Spencer Nielson, Santosh Kumar Muddana, Peter Barabas, Balamurali K. Ambati, Alan W. Stitt, Lara S Carroll, Christina L. O’Neil, Gou Y. Koh, Maggie Marie Flood, and Hironori Uehara
- Subjects
Pathology ,medicine.medical_specialty ,Complications ,Recombinant Fusion Proteins ,Endocrinology, Diabetes and Metabolism ,Genetic enhancement ,Population ,Blood–retinal barrier ,Ischemia ,Inflammation ,Cartilage Oligomeric Matrix Protein ,Retina ,Random Allocation ,chemistry.chemical_compound ,Angiopoietin-1 ,Human Umbilical Vein Endothelial Cells ,Leukocytes ,Internal Medicine ,medicine ,Animals ,Humans ,education ,Cells, Cultured ,Crosses, Genetic ,Endothelial Progenitor Cells ,education.field_of_study ,Diabetic Retinopathy ,Protein Stability ,business.industry ,Retinal ,Genetic Therapy ,Diabetic retinopathy ,medicine.disease ,Combined Modality Therapy ,Mice, Mutant Strains ,3. Good health ,Mice, Inbred C57BL ,Disease Models, Animal ,Diabetes Mellitus, Type 1 ,medicine.anatomical_structure ,Solubility ,chemistry ,Intravitreal Injections ,Immunology ,medicine.symptom ,business - 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.
- Published
- 2015
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