A New Protein Shows Promise for the Treatment and Perhaps Even Prevention of Diabetic Eye Disease

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Although there have been a number of significant advances in the treatment of diabetic eye disease, including Avastin, Lucentis, and Eylea injections, this approach has not proven to be effective in preventing the development of diabetic eye disease and proliferative diabetic retinopathy (explained below).

Recently, however, a research group from the United States and China has discovered a new protein that, when used in combination with current treatments for diabetic eye disease, may prove to be effective in the treatment and possibly prevention of proliferative diabetic retinopathy and other retinal diseases.

From Proceedings of the National Academy of Sciences

The research, entitled Angiopoietin-like 4 is a potent angiogenic factor and a novel therapeutic target for patients with proliferative diabetic retinopathy (all explained below) has been published in the May 26, 2015 Early Edition of Proceedings of the National Academy of Sciences. Proceedings, first published in 1915, is the official journal of the National Academy of Sciences of the United States. It publishes research reports, commentaries, and reviews that span the biological, physical, and social sciences.

The authors are Savalan Babapoor-Farrokhran, Kathleen Jee, Brooks Puchner, Syed Junaid Hassan, Xiaoban Xin, Murilo Rodrigues, Fabiana Kashiwabuchi, Tao Ma, Ke Hu, Monika Deshpande, Yassine Daoud, Sharon Solomon, Adam Wenick, Gerard A. Lutty, Gregg L. Semenza, Silvia Montaner, and Akrit Sodhi, who represent the following institutions: Johns Hopkins University School of Medicine, Baltimore, MD; the University of Maryland, Baltimore; and Chongqing Medical University, China.

About Diabetic Eye Disease and 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.

In addition, fluid can leak into the macula, the small sensitive area in the center of the retina that provides detailed vision. This fluid can cause macular edema (or swelling), which can occur at any stage of diabetic retinopathy, although it is more likely to occur as the disease progresses.

Anti-Angiogenic Drugs and Anti-VEGF Treatments

Angiogenesis is a term used to describe the growth of new blood vessels and plays a crucial role in the normal development of body organs and tissue. Sometimes, however, excessive and abnormal blood vessel development can occur in diseases such as cancer (tumor growth) and retinal disease.

Substances that stop the growth of these excessive blood vessels are called anti-angiogenic (anti=against; angio=vessel; genic=development), and anti-neovascular (anti=against; neo=new; vascular=blood vessels).

The focus of current anti-angiogenic drug treatments for retinal disease is to reduce the level of a particular protein (vascular endothelial growth factor, or VEGF) that stimulates abnormal blood vessel growth in the retina and macula; thus, these drugs are classified as anti-VEGF treatments and are administered by injection directly into the eye after the surface has been numbed.

At present, these anti-VEGF drugs (Lucentis, Avastin, and Eylea) require monthly injections or a pro re nata [meaning "as needed"] (PRN) regimen, with monthly controls and injections for recurrent or persistent blood vessel growth and retinal bleeding.

About the Research

Excerpted from New way to prevent diabetes-associated blindness, via R&D Magazine:

Reporting on their study with lab-grown human cells, researchers … say that blocking a second blood vessel growth protein, along with one that is already well-known, could offer a new way to treat and prevent [diabetic retinopathy] a blinding eye disease caused by diabetes.

Sealing eye blood vessels with laser treatment can save central vision, but this often sacrifices peripheral and night vision, according to [contributing author] Akrit Sodhi, MD, PhD. Several recently developed drugs—Lucentis, Avastin, and Eylea—can help treat these blood vessels by blocking the action of VEGF, a so-called growth factor released as part of a chain of signals in response to low oxygen levels, which stimulates the growth of new, often abnormal, blood vessels. But studies have shown that although these drugs slow progression to proliferative diabetic retinopathy, they do not reliably prevent it.

Looking for an explanation, [the researchers] tested levels of VEGF in samples of fluid from the eye taken from (a) healthy people; (b) people with diabetes who did not have diabetic retinopathy; and (c) people with diabetic retinopathy of varying severity.

While levels of VEGF tended to be higher in those with proliferative diabetic retinopathy, some of their fluid had less VEGF than did the healthy participants. But even the low-VEGF fluid from patients with proliferative diabetic retinopathy stimulated blood vessel growth in lab-grown cells. "The results suggested to us that although VEGF clearly plays an important role in blood vessel growth, it's not the only factor," Sodhi says.

A series of experiments in lab-grown human cells and mice revealed a second culprit, a protein called angiopoietin-like 4 (ANGPTL4). When the researchers blocked the action of both VEGF and angiopoietin-like 4 in fluid from the eyes of people with proliferative diabetic retinopathy, it markedly reduced blood vessel growth in lab-grown cells.

If a drug can be found that safely blocks the second protein's action in patients' eyes, it might be combined with the anti-VEGF drugs to prevent many cases of proliferative diabetic retinopathy, Sodhi suggests. The research team is now investigating whether angiopoietin-like 4 might also play a role in other eye diseases, such as macular degeneration.

More about the Study from Proceedings of the National Academy of Sciences

Excerpted from the abstract of the full article (pdf):

Diabetic eye disease is the most common cause of severe vision loss in the working-age population in the developed world, and proliferative diabetic retinopathy (PDR) is its most vision-threatening sequela [i.e., aftereffect of a disease, condition, or injury].

Therapies targeting vascular endothelial growth factor (VEGF) delay the development of neovascularization in some, but not all, diabetic patients, implicating additional factor(s) in PDR.

Here we demonstrate that the angiogenic potential of aqueous fluid from PDR patients is independent of VEGF concentration, providing an opportunity to evaluate the contribution of other angiogenic factor(s) to PDR development. We identify angiopoietin-like 4 (ANGPTL4) as a potent angiogenic factor.

Expression of ANGPTL4 was increased in the aqueous and vitreous of PDR patients, independent of VEGF levels, correlated with the presence of diabetic eye disease, and localized to areas of retinal neovascularization.

Collectively, our results suggest that targeting both ANGPTL4 and VEGF may be necessary for effective treatment or prevention of PDR and provide the foundation for studies evaluating aqueous ANGPTL4 … to help guide individualized therapy for diabetic eye disease.

Additional Information


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