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Growth Hormone Antagonist May Prevent Some Eye Diseases

Ohio University

ATHENS, Ohio -- Studies of a growth hormone antagonist invented by Ohio University researchers suggest the antagonist may prevent a destructive form of several eye diseases, including diabetic retinopathy.

In a study published in the June 13 issue of the journal Science, researchers at Harvard Medical School, Ohio University and Merck Research Laboratories reported findings that confirm a link between growth hormone and the onset of retinal neovascularization, an end stage in many forms of eye disease that causes blindness in millions of Americans each year.

The study also was presented June 11 at the 79th Annual Meeting of the Endocrine Society in Minneapolis.

Researchers at Harvard Medical School induced retinal neovascularization in mice genetically engineered by scientists at Ohio University to produce a growth hormone antagonist and in normal mice treated with a drug that inhibited growth hormone production. The scientists found there was a 33 to 44 percent decrease in eye disease when growth hormone was decreased or blocked.

"It's been suggested for some time that growth hormone is somehow involved with the onset and progression of diabetic eye disease. This study seems to confirm that," said John Kopchick, Goll-Ohio Professor of molecular biology at Ohio University. Kopchick led a team of scientists with the university's Edison Biotechnology Institute who invented the growth hormone antagonist and the transgenic mice used in this new study.

The findings suggest the use of a growth hormone antagonist or a drug that inhibits growth hormone release may help people with retinal neovascularization, said Lois Smith, professor of ophthalmology at Boston's Children's Hospital and Harvard Medical School and the lead researcher on the project.

Retinal neovascularization occurs when there is an overall decrease in the number of retinal blood vessels, along with reduction in blood flow. Responding to the lack of oxygen, the retina produces new blood vessels. But unlike new blood vessel growth in other parts of the body, neovascularization in the retina can cause damage. New vessels are prone to leakage and bleeding, which blocks light from reaching the retina. This can lead to scarring, which may cause the retina to detach from the inside surface of the eye, leading to blindness.

Retinal neovascularization is seen in people with proliferative -- or, end-stage -- diabetic retinopathy, the leading cause of new cases of blindness in the United States in people age 20 to 64. Abnormal retinal blood vessel growth is also the cause of blindness in retinopathy of prematurity, a condition in some babies, usually born at 30 weeks gestation or earlier, and in age-related macular degeneration in the elderly.

For her studies, Smith placed 7-day-old transgenic and nontransgenic mice in a high-oxygen environment to cause a loss of blood vessels that mimics what happens in babies with retinopathy of prematurity -- high amounts of oxygen stop retinal blood vessel growth and cause some retinal blood vessels to disappear. When returned to normal air conditions, the retinas are oxygen-starved, a condition also seen in diabetic patients with proliferative retinopathy.

"We counted the numbers of abnormal blood vessels in the retina, and there was a significant reduction of neovascularization in the growth hormone antagonist transgenic mice as well as in normal mice treated with a drug that inhibits growth hormone release," Smith said. "We also saw more development of normal blood vessels in the retinas of the transgenic mice compared to the nontransgenic mice."

The findings suggest a growth hormone antagonist or a drug that inhibits growth hormone release has the potential to be used to help prevent retinal neovascularization as well as a treatment for the disorder, but Smith noted more clinical studies are necessary before this group of drugs can be prescribed for patients.

Smith and Kopchick began their collaborations in 1994.

"Dr. Kopchick's understanding of the function and structure of growth hormone and the development of the transgenic mice was a multi-year project in itself. The application of basic knowledge in chemistry and ophthalmology to the creation of a mouse model to study eye diseases also has taken me many years, as has the development of a drug to inhibit growth hormone release," Smith said. "When we put these together, we were able to create a way to study these diseases that none of us could do alone."

Kopchick's research team began work on human growth antagonist in the late 1980s. Human and animal growth hormone contains a chain of 191 amino acids. The researchers discovered that if they replaced the amino acid glycine -- number 119 in the chain in animals and 120 in humans -- with almost any other amino acid, the growth hormone is converted from a growth hormone agonist, or enhancer, to a growth hormone antagonist, or inhibitor.

They replaced the amino acid at the DNA level and generated the growth hormone antagonist and transgenic mice used in the study.

Additionally, in 1995, Ohio University researchers collaborated with scientists at the National Institutes of Health on a study that found that the growth hormone antagonist inhibited the onset of diabetic nephropathy, or kidney disease.

"Our collaborations over the last few years, which suggest a strong link between growth hormone and diabetic nephropathy and diabetic retinopathy, will allow us to further evaluate our plans for the development of a growth hormone antagonist drug for use in treatment of these and other diseases," Kopchick said.

Ohio University patented the growth hormone antagonist in 1994. Sensus Drug Development Corp. in Austin, Texas, holds the license for the invention and currently is using the technology to develop drugs for human diseases in which growth hormone is elevated or diseases in which growth hormone has been implicated.

The research was supported by the National Institutes of Health, Sensus Drug Development Corp., the State of Ohio Eminent Scholar Program and the V. Kann Rasmussen Foundation.

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