Gene therapy may be a tool to prevent blindness

September 10, 2001

Reduces blinding blood vessel growth by up to 90 percent in laboratory mice

Gene therapy may one day be used to halt or even prevent the overgrowth of blood vessels in the eye that blinds patients with macular degeneration and diabetic retinopathy, according to two recent studies led by researchers at Johns Hopkins' Wilmer Eye Institute.

In the studies, performed with laboratory mice, two different genes that were separately injected into the tail veins or eyes of the animals reduced new blood vessel growth by up to 90 percent. One gene is for endostatin, which inhibits blood vessel growth; the other is a substance that increases cell survival. The mice had conditions similar to macular degeneration and diabetic retinopathy, the leading causes of blindness in older and younger people, respectively, in developed countries.

"These studies show that when therapeutic genes are introduced before the stimulus for abnormal blood vessel growth, they partially prevent the abnormal vessels from growing," says Peter A. Campochiaro, M.D., senior author of the studies and a professor of ophthalmology and neuroscience at Hopkins. "While the substances we tested certainly need further study, results are very exciting and demonstrate that gene therapy might provide a promising approach for the treatment of these conditions."

Current therapies for macular degeneration and diabetic retinopathy include laser treatment or surgery to eliminate the abnormal blood vessels. But, in addition to risks associated with surgery, the treatments do nothing to attack the underlying stimuli for blood vessel growth, Campochiaro says.

"As a result, the blood vessels tend to come back," he says. "Even with initially successful treatments, many patients still end up with severe loss of vision."

For the first study, published in the July issue of the American Journal of Pathology, Campochiaro and colleagues packaged the gene for endostatin - a substance that has been reported to inhibit abnormal blood vessel growth in tumors - in a synthetic viral carrier and injected it into the tail veins of mice. The mice were then given a laser treatment that causes abnormal blood vessels to grow from the middle or choroid layer of the eye into the retina, the light-sensitive tissue in back of the eye responsible for vision. The same type of blood vessel growth occurs with macular degeneration. The virus carrier entered liver and other cells in the body. They incorporated the gene, started to make endostatin and secreted it into the bloodstream.

Endostatin reduced the growth of abnormal blood vessels in the eye by 50 percent, scientists observed. By contrast, when an empty virus was injected, no inhibition of abnormal blood vessel growth occurred. Overall, the more endostatin the mice had in their bloodstream, the lower the amount of new blood vessel growth in the eyes.

"Considerable controversy has risen in the past about whether endostatin really inhibits blood vessel growth," Campochiaro says. "This study clearly shows that it can in the eye, and supports previous studies that have suggested inhibition of tumor blood vessels. Further work is needed, however, to ensure that endostatin produced in the body doesn't adversely affect other organs."

In the second study, published in the August issue of the Journal of Cellular Physiology, scientists injected the rodents' eyes with viral vectors containing the gene for pigment epithelium-derived factor (PEDF) - a protein naturally found in the eye that promotes survival of retinal and other nerve cells. The mice were tested in three different models of abnormal blood vessel growth. The first was the same model as used in the endostatin experiments; the other two were models of diabetic retinopathy, in which abnormal blood vessels grow on and within the retina.

In the first model, scientists observed that PEDF injected in front of the retina reduced abnormal blood vessel growth by an average of 50 percent, but injected under the retina, close to faulty blood vessels, reduced overgrowth by an average of 65 percent.

In the other two models, the PEDF gene was even more effective, reducing abnormal blood vessel growth in the retina by 90 percent. With the PEDF vector injected directly into the eye, the rest of the body is spared the exposure to high levels of PEDF.
The first study was supported in part by the U.S. Public Health Service, the National Eye Institute, the Juvenile Diabetes Foundation, Research to Prevent Blindness and CIBA Vision Inc., a division of Novartis Ltd. Pharmaceuticals. Other authors were Keisuke Mori, Akira Ando, Peter Gehlbach, David Nesbitt, Kyoichi Takahashi, Keiko Mori and Michele Melia of Hopkins; and Donna Goldsteen, Michael Penn, Cheauyan T. Chen, Sandrina Phipps, Diana Moffat, Kim Brazzell, Gene Liau and Katharine H. Dixon of Genetic Therapy Inc.

The second study was sponsored in part by the Juvenile Diabetes Foundation and the National Eye Institute. Other authors were Keisuke Mori, Elia Duh, Peter Gehlbach, Akira Ando, Kyoichi Takahashi, Joel Pearlman, Keiko Mori, Hoseong S. Yang and Donald J. Zack of Hopkins; and Damodar Ettyreddy, Douglas E. Brough and Lisa L. Wei of GenVec Inc.

Campochiaro is a paid consultant to CIBA Vision Corp., a division of Novartis Ltd. Pharmaceuticals. The terms of this arrangement are being managed by The Johns Hopkins University in accordance with its conflict-of-interest policies.

Mori, K., et al., "Inhibition of Choroidal Neovascularization by Intravenous Injection of Adenoviral Vectors Expressing Secretable Endostatin," American Journal of Pathology, 159: 313-320.

Mori, K., et al., "Pigment Epithelium-Derived Factor Inhibits Retinal and Choroidal Neovascularization," Journal of Cellular Physiology, 188: 253-263.

Related Web sites:

Wilmer Eye Institute at Johns Hopkins:
Dr. Campochiaro's laboratory:
GenVec, Inc.:
Novartis Pharmaceuticals:
National Eye Institute:
Research to Prevent Blindness, Inc.:

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