New Genetic Research in Diabetes Identifies a Protein That May Stop or Reduce Abnormal Blood Vessel Growth in the Retina

retina with diabetic retinopathy — A retina with diabetic
retinopathy

New genetic research in diabetes, led by a team from Harvard Medical School, has identified a potential new therapy targeting RUNX1 (explained below) that significantly reduced abnormal blood vessel growth in the retina, which is a hallmark of advanced diabetic eye disease.

Although the research has been conducted only with “in vitro” (explained below) laboratory studies of human retinal cells and mouse retinas, the study authors are “hopeful” that inhibiting RUNX1 may also help manage abnormal retinal blood vessel growth in a number of other eye conditions – such as wet macular degeneration and retinopathy of prematurity – earlier in the disease process, before the abnormal blood vessels have a chance to develop.

“We’re hopeful that we may have an opportunity to change the treatment paradigm for these conditions,” said co-author Leo A. Kim, M.D., Ph.D. “Instead of treating patients after these abnormal blood vessels form in the eye, we may be able to give patients eye drops or systemic medications that prevent their development in the first place.”

The Research from Diabetes

This new diabetes research, titled Identification of RUNX1 as a Mediator of Aberrant Retinal Angiogenesis (Translation: Identification of a protein that can change or reduce the abnormal blood vessel growth that occurs in retinal disease, including diabetic retinopathy), has been published “online first” on April 11, 2017, in Diabetes, published by the American Diabetes Association. Diabetes presents original research about the normal and abnormal physical processes that occur with diabetes mellitus, including laboratory, animal, and human research.

The authors are Jonathan D. Lam, Daniel J. Oh, Lindsay L. Wong, Dhanesh Amarnani, Cindy Park-Windhol, Angie V. Sanchez, Jonathan Cardona-Velez, Declan McGuone, Anat O. Stemmer-Rachamimov, Dean Eliott, Diane R. Bielenberg, Tave van Zyl, Lishuang Shen, Xiaowu Gai, Patricia A. D’Amore, Leo A. Kim, and Joseph F. Arboleda-Velasquez, from Harvard Medical School, Boston, MA; Massachusetts General Hospital, Boston, MA; Children’s Hospital Los Angeles, Los Angeles, CA; and Universidad Pontificia Bolivariana, Medellin, Colombia.

First, Some Terminology Used in the Research

Here is a brief explanation of some key terms used in this diabetes research:

Angiogenesis: Describes the growth of new blood vessels and plays a crucial role in the normal development of body organs and tissue. However, excessive and abnormal blood vessel development can also occur in diseases such as cancer (tumor growth), macular degeneration, and diabetic retinopathy (retinal and macular bleeding).
In vitro: Refers to processes taking place in a test tube or culture dish, typically in a laboratory. “In vivo” refers to processes taking place in a living human or other organism.
Neovascularization: When referring to the eye, as in diabetic retinopathy and wet age-related macular degeneration, it describes abnormal blood vessel growth in the retina (neo = new; vascular = blood vessels). Neovascularization is also a feature of other eye and health conditions, including retinopathy of prematurity and cancer.
RUNX1: Runt-related transcription factor 1, a protein that in humans is encoded by the RUNX1 gene. The RUNX1 protein activates genes that help control the development of blood cells.
VEGF: A protein, called vascular endothelial growth factor, that stimulates abnormal blood vessel growth in the retina and macula.

About the Research

Excerpted from Researchers identify new target for abnormal blood vessel growth in the eyes, via Medical Xpress:

[Researchers] have identified a novel therapeutic target for retinal neovascularization, or abnormal blood vessel growth in the retina, a hallmark of advanced diabetic eye disease (proliferative diabetic retinopathy).

… the transcription factor RUNX1 was found in abnormal retinal blood vessels, and by inhibiting RUNX1 with a small molecule drug, the researchers achieved a 50 percent reduction of retinopathy in preclinical [meaning before human clinical trials have begun] models. These findings pave the way for new therapies that address diabetic retinopathy and other conditions involving abnormal vessel growth within the retina.

“Current treatments to control retinal neovascularization require injecting very large proteins [i.e., Lucentis, Eylea, and Avastin] … into the eyes of patients, as often as once a month. Our study opens the door for novel modes of treatment based on small molecules that could cross biological barriers on their own. Such a treatment could be self-administered by patients and eliminate the need for intravitreal injections,” said co-author Joseph F. Arboleda-Velasquez, M.D., Ph.D.

In the Diabetes report, the authors studied tissue from patients with proliferative diabetic retinopathy. They identified the presence of RUNX1 in the diseased blood vessels but not in the normal blood vessels. Next, they used a small molecule drug originally developed as a cancer therapy to inhibit the activity of RUNX1 in the eye, which led to a significant reduction of abnormal blood vessels.

The study authors are hopeful that inhibiting RUNX1 may present a more targeted opportunity for managing the retinopathy of certain eye conditions—perhaps earlier in the disease process, before the abnormal blood vessels develop. Future studies will test whether the drug can be delivered through topical eye drops rather than by injection, and further explore the relationship between RUNX1 and VEGF, as these factors seemingly both play a role in angiogenesis.

More about Diabetic Eye Disease

Diabetic Retinopathy

Although people with diabetes are more likely to develop cataracts at a younger age and are twice as likely to develop glaucoma as people who do not have diabetes, the primary vision problem caused by diabetes is diabetic retinopathy, the leading cause of new cases of blindness and low vision in adults aged 20-65:

“Retinopathy” is a general term that describes damage to the retina.
The retina is a thin, light-sensitive tissue that lines the inside surface of the eye. Nerve cells in the retina convert incoming light into electrical impulses. These electrical impulses are carried by the optic nerve to the brain, which interprets them as visual images.
Diabetic retinopathy occurs when there is damage to the small blood vessels that nourish tissue and nerve cells in the retina.
“Proliferative” is a general term that means to grow or increase at a rapid rate by producing new tissue or cells. When the term “proliferative” is used in relation to diabetic retinopathy, it describes the growth, or proliferation, of abnormal new blood vessels in the retina. “Non-proliferative” indicates that this process is not yet occurring.
Proliferative diabetic retinopathy affects approximately 1 in 20 individuals with the disease.

Four Stages of Diabetic Retinopathy

According to the National Eye Institute, diabetic retinopathy has four stages:

Mild non-proliferative retinopathy: At this early stage, small areas of balloon-like swelling occur in the retina’s tiny blood vessels.
Moderate non-proliferative retinopathy: As the disease progresses, some blood vessels that nourish the retina become blocked.
Severe non-proliferative retinopathy: Many more blood vessels become blocked, which disrupts the blood supply that nourishes the retina. The damaged retina then signals the body to produce new blood vessels.
Proliferative retinopathy: At this advanced stage, signals sent by the retina trigger the development of new blood vessels that grow (or proliferate) in the retina and the vitreous, which is a transparent gel that fills the interior of the eye. Because these new blood vessels are abnormal, they can rupture and bleed, causing hemorrhages in the retina or vitreous. Scar tissue can develop and can tug at the retina, causing further damage or even retinal detachment.

You can learn more about all current treatments for diabetic retinopathy at What Treatments Are Available for Diabetic Eye Disease? at VisionAware.org

More About the Study from the Journal Diabetes

Excerpted from the study Abstract:

Proliferative diabetic retinopathy (PDR) is a common cause of blindness in the developed world’s working adult population, and affects those with type 1 and type 2 diabetes mellitus.

We identified Runt-related transcription factor 1 (RUNX1) as a gene upregulated in CD31+ vascular endothelial cells obtained from human PDR fibrovascular membranes (FVM) via transcriptomic analysis.

In vitro studies using human retinal microvascular endothelial cells (HRMECs) [i.e., cells on the inner lining of blood vessels] showed increased RUNX1 RNA and protein expression in response to high glucose, whereas RUNX1 inhibition reduced HRMEC migration, proliferation, and tube formation.

Immunohistochemical staining for RUNX1 showed reactivity in vessels of patient-derived FVM and angiogenic tufts in the retina of mice with oxygen-induced retinopathy (OIR), suggesting that RUNX1 upregulation is a hallmark of aberrant retinal angiogenesis.

Inhibition of RUNX1 activity with the Ro5-3335 small molecule resulted in a significant reduction of neovascular tufts in oxygen-induced retinopathy (OIR), supporting the feasibility of targeting RUNX1 in aberrant retinal angiogenesis.