Intravitreal AAV2.COMP-Ang1 Prevents Neurovascular Degeneration in a Murine Model of Diabetic Retinopathy.
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.
Department of Ophthalmology and Visual Sciences, John A. Moran Eye Center, University of Utah, Salt Lake City, UT.
Judd M
JM
Cahoon
Department of Ophthalmology and Visual Sciences, John A. Moran Eye Center, University of Utah, Salt Lake City, UT.
Ruju R
RR
Rai
Department of Ophthalmology and Visual Sciences, John A. Moran Eye Center, University of Utah, Salt Lake City, UT.
Lara S
LS
Carroll
Department of Ophthalmology and Visual Sciences, John A. Moran Eye Center, University of Utah, Salt Lake City, UT.
Hironori
H
Uehara
Department of Ophthalmology and Visual Sciences, John A. Moran Eye Center, University of Utah, Salt Lake City, UT.
Xiaohui
X
Zhang
Centre for Vision and Vascular Science, Queen's University Belfast, Belfast, Ireland.
Christina L
http://orcid.org/0000-0002-7546-5510
CL
O'Neil
Centre for Vision and Vascular Science, Queen's University Belfast, Belfast, Ireland.
Reinhold J
RJ
Medina
Department of Ophthalmology and Visual Sciences, John A. Moran Eye Center, University of Utah, Salt Lake City, UT.
Subtrata K
SK
Das
Department of Ophthalmology and Visual Sciences, John A. Moran Eye Center, University of Utah, Salt Lake City, UT.
Santosh K
SK
Muddana
Department of Ophthalmology and Visual Sciences, John A. Moran Eye Center, University of Utah, Salt Lake City, UT.
Paul R
PR
Olson
Department of Ophthalmology and Visual Sciences, John A. Moran Eye Center, University of Utah, Salt Lake City, UT.
Spencer
S
Nielson
Department of Ophthalmology and Visual Sciences, John A. Moran Eye Center, University of Utah, Salt Lake City, UT.
Kortnie
K
Walker
Department of Ophthalmology and Visual Sciences, John A. Moran Eye Center, University of Utah, Salt Lake City, UT.
Maggie M
MM
Flood
Department of Ophthalmology and Visual Sciences, John A. Moran Eye Center, University of Utah, Salt Lake City, UT.
Wyatt B
WB
Messenger
Department of Ophthalmology and Visual Sciences, John A. Moran Eye Center, University of Utah, Salt Lake City, UT.
Bonnie J
BJ
Archer
Department of Ophthalmology and Visual Sciences, John A. Moran Eye Center, University of Utah, Salt Lake City, UT.
Peter
P
Barabas
Department of Ophthalmology and Visual Sciences, John A. Moran Eye Center, University of Utah, Salt Lake City, UT.
David
D
Krizaj
Department of Biomedical Engineering, University of Utah, Salt Lake City, UT.
Christopher C
CC
Gibson
Program in Molecular Medicine, Department of Medicine, University of Utah, Salt Lake City, UT.
Dean Y
DY
Li
Korean Advanced Institute for Science and Technology, Daejeon, South Korea.
Gou Y
GY
Koh
Department of Molecular Genetics and Microbiology, University of Massachusetts, Worcester, MA.
Guangping
G
Gao
Centre for Vision and Vascular Science, Queen's University Belfast, Belfast, Ireland.
Alan W
AW
Stitt
Department of Ophthalmology and Visual Sciences, John A. Moran Eye Center, University of Utah, Salt Lake City, UT bala.ambati@utah.edu.
Balamurali K
BK
Ambati
D042683:Angiopoietin-1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D000818:Animals; D064236:Cartilage Oligomeric Matrix Protein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D002478:Cells, Cultured; D003131:Combined Modality Therapy / Q000009:adverse effects; D003433:Crosses, Genetic; D003922:Diabetes Mellitus, Type 1 / Q000150:complications*; D003930:Diabetic Retinopathy / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D004195:Disease Models, Animal; D066026:Endothelial Progenitor Cells / Q000166:cytology / Q000637:transplantation; D015316:Genetic Therapy / Q000009:adverse effects; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D006801:Humans; D058449:Intravitreal Injections; D007962:Leukocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D055550:Protein Stability; D011897:Random Allocation; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use; D012160:Retina / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D012995:Solubility
D042683:Angiopoietin-1; D064236:Cartilage Oligomeric Matrix Protein; D011993:Recombinant Fusion Proteins; C467630:ANGPT1 protein, human; C577553:TSP5 protein, human