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Two recent discoveries from the University of Utah School of Medicine and the affiliated John A. Moran Eye Center, in collaboration with researchers from other locations, are providing new hope to those suffering from age-related macular degeneration and diabetic retinopathy.

In the first study, which focused on impacting the two conditions in mice models, researchers found that damage could be prevented and even reversed by activating the protein Robo4. The second study identified the gene erythropoietin (EPO) as being linked to increased risk of severe diabetic retinopathy and nephropathy and suggested potential courses of action to mitigate the increased susceptibility of those carrying the gene.

Dr. Kang Zhang, PhD, associate professor of ophthalmology and director of ophthalmic genetics at the University of Utah’s John A. Moran Eye Center, served as senior author on the EPO study and co-author and collaborator on the Robo4 study, which was led by colleague, Dr. Dean Li, PhD.

“Essentially, we found a counter mechanism for the body to respond to the pathological angiogenesis, which is a hallmark of the two major causes of blindness –– wet age-related macular degeneration and diabetic retinopathy,” explained Zhang.

He added that wet AMD is the leading cause of vision loss in Americans age 65 and over, while diabetic retinopathy is the leading cause of blindness in working-age adults. Zhang noted that between the two, more than 15 million Americans are at risk of losing their eyesight.

While blood vessel growth is important to healthy function, overproduction at the wrong time or in the wrong place often leads to blood vessels that are unstable and weak.

Although wet AMD does have an effective treatment in anti-vascular endothelial growth factor (VEGF) therapy (ranibizumab or bevacizumab), Zhang said, “The catch is not everyone responds perfectly so it would be important to find a combination therapy that would help people respond better.”

Robo4, which is only found in the interior surface cells of blood vessels, is activated by a protein called Slit. When activated in mice models, Robo4 inhibited abnormal blood vessel growth and stabilized blood vessels to prevent leakage, two primary factors in both wet AMD and diabetic retinopathy.

“We made a small protein fragment that could easily be injected into the mouse eye,” explained Zhang. “We plan to use the same strategy to inject the molecule into the human eye to stop abnormal blood vessel growth and bleeding.”

He added that part of the human trial will be to figure out dosing and the amount of protein needed to achieve the desired results. Although human studies have not yet commenced, Zhang said it is possible the drug could be on the market in about five years if trials progress as expected.

While this specific study focused on the eyes, Li said the ramifications could extend to other conditions, as well.

“Many diseases are caused by injury or inflammation destabilizing blood vessels and causing them to leak fluid into adjacent tissues, as well,” he said in announcing the study’s findings. “We found a natural pathway –– the Robo4 pathway –– that counterattacks this by stabilizing blood vessels.”

Hemin Chin, PhD, director of the ocular genetics program at the National Eye Institute, said this discovery is a prime example of basic science research yielding a discovery with direct clinical application.

The second study, on which Zhang’s laboratory took the lead, focused on the function of well-known gene EPO on proliferative diabetic retinopathy (PDR) and end-stage renal disease (ESRD).

In announcing his lab’s discovery, Zhang said, “We know that the development of PDR and ESRD in diabetic patients can be inherited. Although genetic factors are known to be important in the susceptibility (or resistance) to these complications, until now the genes involved have been mostly unknown.”

Researchers compared nearly 2,000 diabetic patients with PDR and ESRD to a similar number of diabetics without eye and kidney complications. The team found that those with a mutant EPO gene had an increased risk of developing PDR and ESRD during their lifetime.

Currently, exogenous EPO is used frequently to assist in the production of red blood cells in patients who are anemic, typically those with chemotherapy-induced anemia or renal disease. A significant number of patients with renal disease are also diabetic and could, therefore, be at higher risk of PDR and ESRD.

Zhang said their study added to the body of evidence that for diabetics on EPO, the higher hemoglobin comes with a higher rate of complications.

“We were able to pinpoint the genetic variance,” he noted.

Once researchers knew what variation to seek, they were able to create a relatively simple test to highlight the single nucleotide polymorphism. Zhang said once the assay is set up, it takes less than an hour to identify whether or not the patient has the mutant copy of the gene.

“There are two implications,” Zhang continued. “Now EPO becomes a target for treatment … we should be able to block EPO and reduce the complications of diabetic retinopathy.”

The second implication is for patients on dialysis receiving erythropoietin.

“We need to be careful of giving people EPO who are on dialysis because it might accelerate end stage renal disease,” he cautioned.

Zhang added that identifying which patients are at increased risk through genetic testing plus careful monitoring of eye and kidney function should help clinicians in their efforts to maintain a balance between keeping patients from being anemic and pushing them over the edge to further complications.

The good news coming out of these two studies is that researchers now know more about blood vessel growth and bleeding and have promising lines for follow-up research on effective therapies.

“If you have lots of EPO or lots of VEGF, you are going to have bleeding,” Zhang concluded. “So Robo might block that … that’s one strategy. The other strategy is to block EPO … or maybe a combination (of the two) might make them both more potent.”

For the millions in danger of losing their sight to wet AMD or diabetic retinopathy, having a better understanding of genetic risk and potential new options for treatment is certainly worth a second look.



July 2008

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