Intraocular Therapy Prevents or Reverses Diabetic Retinopathy in Mice

Agent leads to overexpression of angiotensin converting enzyme-2, according to a new report in The American Journal of Pathology

Philadelphia, PA, May 10, 2016

Pathologic changes of the retina caused by diabetes is the leading cause of blindness in working adults. Diabetic retinopathy has no known cure, treatment options are inadequate, and prevention strategies offer limited protection. In the first of its kind, a report in The American Journal of Pathology describes a potential new intraocular treatment based on manipulating the renin angiotensin system (RAS) that both prevents and reverses some characteristics of diabetic retinopathy in a mouse model.

“We are not aware of another study that has demonstrated a therapy capable of reversing this form of retinal pathology, particularly in the presence of persistent untreated hyperglycemia,” commented lead investigator Maria B. Grant, MD, of the Eugene and Marilyn Glick Eye Institute of Indiana University, Indianapolis, IN.

“This research is based on the hypothesis that an imbalance between two axes of the RAS is a key initial event that leads to development of diabetic microvascular complications,” explained Dr. Grant. The two axes consist of the classic and vasoprotective RAS. The proinflammatory, vasoconstrictive classical RAS component is normally kept in check by a vasoprotective axis that is both anti-inflammatory and vasodilatory. Angiotensin converting enzyme-2 (ACE-2) is the primary enzyme of the vasoprotective component. Administration of AAV-ACE—the therapeutic agent under evaluation—directly into the vitreous cavity of the eye using an adeno-associated virus vector, increases ACE-2 expression.

Investigators used mice, some of which were injected with streptozotocin (STZ) to induce diabetes. The protective effects of AAV-ACE2 were examined by performing two sets of experiments. In one cohort, AAV-ACE2 was administered two weeks prior to STZ injection. In a second cohort, to evaluate whether the enhanced expression of ACE2 could reverse diabetic retinopathy, AAV-ACE2 was administered six months after STZ, when diabetes and retinopathy were already established.

Diabetic Retinopathy

Reversal cohort— ACE2 administration reverses the increase of infiltrating inflammatory cells in diabetic mice. Retinas from nondiabetic (top panels) or diabetic (bottom panels) animals that received either AAV-ACE2 injection (right panels) or AAV alone (control). Inflammatory macrophage/microglial cells, which are significantly higher in the untreated diabetic group (bottom left panel) compared to all other groups. Yellow arrowheads: F4/80-GFP. Red arrowheads: F4/80-positive.

The investigators found that both strategies effectively decreased the numbers of proinflammatory cells present in the diabetic retina. Leukostasis—abnormal aggregation and clumping of white blood cells within blood vessels—was only seen in diabetic animals receiving control injections. In addition, using a histological endpoint of retinal vascular degeneration, called acellular capillaries, the group determined that the AAV-ACE2 injection could reverse the diabetes-induced pathology. “These findings are very exciting because it is traditionally believed that this endpoint of vascular degeneration, acellular capillaries, represents an irreversible lesion,” emphasized Dr. Grant.

One strength of this experimental approach is that intravitreal administration eliminates the problem of the blood-retinal barrier interfering with access of systemically-administered therapeutic agents. The investigators envision that inducing ACE2 overexpression to improve vascular characteristics and decrease inflammation may be translatable to other vascular diseases such as stroke, kidney disease, and heart disease.

Diabetic retinopathy results from pathologic changes to small blood vessels in the retina. Common features are inflammation, leukostasis, and microangiopathy (a condition in which the capillary walls become so thick and weak that they bleed, leak protein, and slow the flow of blood).

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Notes for editors
“Adenoassociated Virus Overexpression of Angiotensin Converting Enzyme-2 Reverses Diabetic Retinopathy in Type 1 Diabetes in Mice,” by James M. Dominguez II, Ping Hu, Sergio Caballero, Leni Moldovan, Amrisha Verma, Gavin Y. Oudit, Qiuhong Li, and Maria B. Grant (doi: 10.1016/j.ajpath.2016.01.023). This article appears online ahead of The American Journal of Pathology, Volume 186, Issue 6 (June 2016) published by Elsevier.

Full text of this study is available to credentialed journalists upon request; contact Eileen Leahy at +1 732 238 3628 or ajpmedia@elsevier.com. Journalists wishing to interview the authors should contact Maria B. Grant at +1 317 274 2628 or mabgrant@iupui.edu.

This research was supported by NIH Grants EY-07739, EY-12601, DK-090730-02, EY-018358, EY 021626, HL-110170, and EY021752. Core facilities were supported by NEI grant P30 EY-02172 and Research to Prevent Blindness.

About The American Journal of Pathology
The American Journal of Pathology, official journal of the American Society for Investigative Pathology, seeks to publish high-quality, original papers on the cellular and molecular biology of disease. The editors accept manuscripts that advance basic and translational knowledge of the pathogenesis, classification, diagnosis, and mechanisms of disease, without preference for a specific analytic method. High priority is given to studies on human disease and relevant experimental models using cellular, molecular, animal, biological, chemical, and immunological approaches in conjunction with morphology.

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The American Journal of Pathology
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