Seeing the Future

and John McIntosh

Retinopathy, a common complication of diabetes, develops because of gradual changes to the retina—a delicate, light-sensitive membrane lining the inner eyeball that is connected to the brain via the optic nerve. When diabetic retinopathy (DR) goes untreated, it can compromise the retina, impair vision and cause blindness.

The sight-damaging changes to the retina may be the result of:

  • Tiny swellings in the wall of retinal blood vessels that appear as small, round, red spots (microaneurysms)
  • Leakage from the blood vessels into the eye (exudates)
  • Bleeding into the vitreous fluid in the center of the eye (hemorrhages)
  • Growth of unstable, new blood vessels (neovascularization or proliferative retinopathy)

Retinopathy Basics Q&A

Fortunately, today we know a great deal about how to control, minimize and prevent diabetic retinopathy. “Recent JDRF-funded studies have deepened our understanding of the damage that elevated glucose levels can cause throughout the body,” says Barbara Araneo, Ph.D., JDRF’s director of complications therapies. “And we know that maintaining control of blood glucose helps reduce the risks of many complications, including eye disease. We even have recent evidence that diabetic eye disease is treatable.”

In addition, JDRF has forged collaborations with academic investigators and biotech companies such as the DRCRnet (Diabetic Retinopathy Clinical Research Network), ActiveSite, Genentech and Asklepios BioPharmaceuticals. These collaborations are investigating exciting new ways to manage retinopathy, improve lost vision and prevent the disease.

Steps for Prevention and Control

Preventing or minimizing retinopathy is, to some extent, in the hands of the person with diabetes and his or her care providers. Establishing good glucose control and controlling blood pressure and cholesterol can go a long way to keeping the small vessels of the eye healthy.

“We spend a lot of time educating individuals to learn about their own disease and to become better advocates for themselves,” says Lloyd Paul Aiello, M.D., Ph.D., professor of ophthalmology at Harvard Medical School, director of the Joslin Diabetes Center’s Beetham Eye Institute and founding chair of the National Eye Institute Diabetic Retinopathy Clinical Research Network, “but it’s really a matter of team work. Health care providers need to make sure that people with diabetes are keeping their appointments and having their blood pressure and cholesterol checked and keeping their glucose in control.”

The benefits are well established. The Diabetes Complications and Control Trial found that intensive therapy (keeping A1Cs to 6% or less) reduced the risk for developing retinopathy by 76 percent. In participants who had some eye damage at the beginning of the study, intensive management slowed the progression of the disease by 54 percent.

“It’s also important to have regular eye exams,” says Dr. Aiello, creator of the Joslin Vision Network, a digital screening program that allows for remote diagnosis. “The earliest signs of retinopathy cause changes an ophthalmologist can see in the retina. And those changes happen long before a patient would notice any symptoms.” If those changes are caught, steps can be taken right away to arrest or slow the progression of the disease.

The American Diabetes Association’s most recent Standards of Care suggests that people with type 1 diabetes begin to have an annual dilated eye examination starting five years after diagnosis. “That’s the recommendation,” says Dr. Aiello. “If you do it, you should be okay. However, I prefer that people do it every year from diagnosis. That helps everyone get into the habit and although it is very, very rare to have any vision-threatening changes in the first five years, it does make sure nothing slips by.”

After that, depending on what is found during the exam, you may come back ever more frequently. “If you have developed, or are just about to develop, proliferative retinopathy, that’s when you need to have photo laser coagulation,” says Dr. Aiello. “That treatment can reduce the risk of severe vision loss by more than 95 percent if administered at the right time.” Diabetic macular edema—traditionally treated with focal laser—is caused by the accumulation of excess fluid in the eye and swelling of the retina; it can happen at any stage of retinopathy, independent of proliferative retinopathy. “People with these types of advanced retinopathy should see their eye doctor every three or four months for tracking, treatment and follow-up,” says Dr. Aiello.

Retinopathy Treatment and Trials

To more effectively prevent or stop the progression of diabetic retinopathy it is necessary to know what causes blood vessels to leak and or proliferate. JDRF is funding investigation into both genetic and biochemical processes that contribute to the development of retinopathy.

The Genetic Connection: Although people with diabetes can do a great deal to protect their eyes, some vision problems may be a result of genetic predispositions that are beyond an individual’s control. In fact, one person may develop diabetic eye disease despite relatively good glucose control because they are genetically programmed to be at high risk for retinopathy, while another may avoid eye disease, even though they maintain poorer glycemic control. For this reason, JDRF and DRCRnet (a collaborative network of more than 200 clinical sites around the world established by the National Institutes of Health to facilitate clinical research on diabetic retinopathy) have formed a partnership to enable study of both the genetic basis of diabetic retinopathy with the intent of learning the factors that control both susceptibility and resistance to this condition.

The Biochemical Connection: Teasing out the elusive biochemical processes that are involved in diabetic retinopathy has led researchers to clinical and animal studies of potential therapies.

Ranibizumab (Lucentis)— a monoclonal antibody that acts as a vascular endothelial growth factor (VEGF) inhibitor
Status: In the U.S., Lucentis (ranibizumab) is not approved for the treatment of diabetic macular edema, but it is approved for the treatment of two other macula-related diseases: wet age-related macular degeneration and macular edema following retinal vein occlusion (RVO). Diabetes is a risk factor for RVO—a condition in which the blood vessel that drains the retina, or one of its branches, is blocked. Other risk factors for RVO include high blood pressure, atherosclerosis, and high cholesterol.

Unlike the U.S., Europe has approved Lucentis for the treatment of diabetic macular edema. However, in the U.S. there are two identical parallel studies designed to support application to the Food & Drug Administration for Lucentis for DME. Recently, Genentech announced that one of these studies, known as RISE, met its primary endpoint. Results showed that a significantly higher percentage of patients receiving monthly Lucentis had an improvement in vision on the eye chart at 24 months, compared to patients in a control group who received a placebo injection.

How it works: Ranibizumab binds to and inhibits vascular endothelial growth factor (VEGF), a protein in the blood that is thought to play an important role in both the growth of new blood vessels and fluid leakage into the eye.

Study results: Two Phase III randomized studies—called BRAVO and CRUISE—found that the benefits of monthly injections of the drug into the fluid that fills the center of the eye (the vitreous fluid) for RVO were notable.

  • Both six-month studies showed a sustained vision improvement early on (at day seven) in patients with macular edema following RVO in the smaller branches of vessels from the main retinal vein.
  • In both studies, 48 to 61 percent of participants receiving Lucentis had at least a 15-letter gain in best-corrected visual acuity. In both, only 1.5 percent of participants reported a loss of visual acuity of 15 letters or more.
  • An analysis of the six-month data from BRAVO and CRUISE showed a safety profile consistent with previous Lucentis trials in wet AMD, with no new safety events identified to date.

JDRF Moving Forward: JDRF has spearheaded investigation into the use of ranibizumab to treat diabetic macular edema (DME), the leading cause of functional visual loss among working Americans.

  • In READ-1 (Ranibizumab for Edema of the Macula in Diabetes, a phase 1 study) Trial, Quan Dong Nguyen, M.D., Peter Campochiaro, M.D., M.Sc., and colleagues at the Wilmer Eye Institute of Johns Hopkins University treated 10 people who had chronic diabetic macular edema using an intravitreal injection of the drug at baseline, as well as at one, two, four and six months. The injections were well-tolerated and the results showed that ranibizumab significantly reduced macular swelling and improved vision. The READ-1 study was supported by the JDRF Innovative Grant awarded to Dr. Nguyen.
  • READ-2 was a multi-center national trial also supported by JDRF, with the study drug provided by Genentech. In it, 126 patients were evaluated for the effectiveness of ranibizumab when compared to laser photocoagulation therapy alone or the combination of laser with ranibizumab. At six months, the primary endpoint of the study, there was significantly greater improvement in vision in patients treated with ranibizumab compared to those receiving laser photocoagulation or a combination of laser and ranibizumab. READ-2 study.
  • The JDRF-funded READ-3 study is investigating the safety, tolerability, and bioactivity of two different doses (0.5mg and 2.0mg) of ranibizumab (Lucentis). Other studies have shown that 0.5 mg intraocular injections of the drug decrease retinal thickness and improve best corrected visual acuity (BCVA) for people with DME. However, studies have shown that repeated injections of ranibizumab at 0.5mg dosages are needed to maintain effectiveness. According to Yasir Sepah, MBBS, a postdoctoral research assistant who works with Dr. Quan at the Retinal Imaging Research and Reading Center at the Wilmer Eye Institute, “We know 0.5mg of ranibizumab decreases diabetic macular edema, but it is also important to determine whether there is any difference in the bioactivity and duration of effect in similar patients when they are treated with the higher 2.0mg dose.”
  • Dr. Nguyen, Dr. Campochiaro and Dr. Diana Do at the Wilmer Eye Institute and 12 other clinician scientists, serving as principal investigators and co-investigators at clinical centers in California, Florida, Hawaii, Illinois, Kansas, Pennsylvania, South Dakota and Texas, are participating in the READ-3 Study. JDRF has partnered with Genentech, Inc., which is providing the study drug. For complete information on READ-3, please go to http://www.read3.net/About_the_Study/default.html
  • The results of the READ-1 and READ-2 studies have served as a foundation for the design and conduct of subsequent Phase III studies in the U.S. and other countries, evaluating the potential role of ranibizumab in the management of DME.

Expanding the Research Circle
Although it is quite effective, this anti-VEGF agent does not work for everyone. “This inhibitor only blocks the VEGF pathway,” explains Dr. Aiello whose research has focused extensively on understanding the mechanisms of VEGF expression. “Now we know there are other pathways.”

So let’s look at that…

Plasma Kallikrein (PK) Inhibitors
Status: Researchers at the Joslin Diabetes Center identified another biochemical, plasma kallikrein, that they believe is also involved in diabetic retinopathy and macular edema. As one part of a normal cascade of enzymes in the body, plasma kallikrein helps regulate certain inflammatory reactions, and in diabetes this pathway may play an important role in damage to the retinal blood vessels and in increased retinal vascular permeability. This pioneering work, supported by a JDRF research grant, was published in Nature Medicine 2007. It was performed in the laboratory of Edward Feener, Ph.D., an investigator at the Joslin Diabetes Center and associate professor of medicine at Harvard Medical School. Further JDRF-funded research conducted in the Feener laboratory, in collaboration with ActiveSite Pharmaceuticals, identified a PK inhibitor, ASP-440, that reduced pathological retinal vascular permeability in rats. This study was published in the February 2009 issue of the journal Hypertension. It demonstrated that continuous systemic administration of ASP-440 was effective in decreasing hypertension-induced increased retinal vascular permeability in rodents by as much as 70 percent. Recent studies presented at the Association for Research in Vision and Ophthalmology (ARVO) meeting in 2010 showed that ASP-440 also reduced retinal vascular permeability in rodents with diabetes.

Hypertension article

How it works: Plasma kallikrein is a circulating protease that, when activated, increases blood vessel inflammation and permeability by generating the production of a hormone called bradykinin. “PK inhibitors are believed to reduce retinal vessel leakage by suppressing the chronic and excessive production of bradykinin.” says Dr. Feener. These insights may shed more light on what happens to the vessels of the retina when retinopathy develops.

Next steps: A new investigation by Dr. Feener, funded by JDRF, will perform further validation studies on the target [the kallikrein pathway] and identify additional strategies to reduce PK pathway activity to enable expanded research on this area. “Data so far shows that PK is present in the vitreous fluid obtained from people with advanced diabetic retinopathy and studies using in diabetic animal models suggest that local activation of this pathway may contribute to retinal dysfunction,” explains Dr. Feener. “But it is critical to be rigorous about this target by testing the long-term and systemic effects of inhibiting the PK pathway on the eye.”

“The emerging research on PK and its inhibitors is important because it gives us an even better understanding of diabetic eye disease and it also offers the opportunity to move forward with the immediate translation of several inhibitors from the lab to the clinic,” says JDRF’s Dr. Araneo.

The Slit-Robo-4 Axis—another door opens for possible therapies
Status: Studies in the lab indicate that the development of diabetic retinopathy may also be related to the activity of a family of so-called guidance molecules, known by the names Slit and Robo-4. These insights are leading researchers to explore how the guidance molecules interact with VEGF (inhibited by Lucentis, see above) and the role they play in the proliferation and leakage of vessels in the eye.

Advanced Experimental Medical Biology abstract.

How it works: “Slit-Robo signaling can inhibit over-exuberant blood vessel growth and vascular permeability that leads to leakage,” says JDRF-funded researcher, Dean Li, M.D., Ph.D., distinguished professor of medicine and of oncological sciences and human genetics at the University of Utah. In an animal model of proliferative retinopathy, Dr. Li and his team have found that manipulating the Slit-Robo axis may reduce the severity of disease.

Looking forward: “Our laboratory uses mice and zebrafish as genetic models and incorporates biochemical signaling and cell culture studies,” explains Dr. Li. But he is focused on translating those findings into therapies that will help prevent human diseases. “The overarching goal,” he says, “is to impact either our understanding and/or treatment of human diseases. We seek to drive our projects toward medical application by building our understanding of the Slit-Robo pathway and examine how it might be advanced for the treatment of diabetic vascular complications in the eye.”