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News

Autoimmune disease weakens eye and body muscles

Case Western Reserve University : 01 February, 2007  (Technical Article)
Under a new $4.7 million grant from the National Eye Institute, researchers from Case Western Reserve University School of Medicine and University Hospitals of Cleveland hope to develop in five years a drug ready for human clinical trials to treat myasthenia gravis, an autoimmune disease that weakens muscles, affects vision, and in the most severe cases, puts patients on artificial ventilation. According to the National Eye Institute, this is the largest single project grant it has awarded to an Ohio institution.
The new grant to Henry J. Kaminski, M.D., a professor in the Department of Neurology and a member of the Visual Sciences Research Center at Case and UHC, brings together a group of experts well-versed in the disease, muscle biology, genetics, and drug development who are associated with Case, UHC and the Louis Stokes Cleveland Department of Veterans Affairs Medical Center.

Among the unique features of this research project is that it will be the first to apply genomic analysis to this disorder and will be the first to comprehensively investigate eye muscle involvement by the disease.

In autoimmune diseases, the immune system malfunctions and mistakes a part of the body as foreign and mounts an attack on it. According to Kaminski, in myasthenia gravis, the immune system produces antibodies that attack the receptors on the muscle side of the neuromuscular junction. The antibodies cause damage by activating another part of the immune system called the complement system, which is a group of proteins designed to protect against infectious invaders.

'We hope to design a drug that inhibits complement activation specifically at the nerve-muscle communication point,' said Kaminski. 'Although there currently are several treatments that are beneficial in treating the disease, they have numerous adverse effects. We hope our treatment would be a more effective one with less side effects.'

Kaminski said that although the disease is relatively rare with a prevalence of about 400 cases in one million people, it is the best-understood autoimmune disease. 'Understanding this disease will likely provide new insights of other disorders,'said Kaminski.

The grant brings together a diverse group of scientists with individual interests in: complement (Edward Medof, M.D., Ph.D., and Feng Lin, Ph.D., both in the pathology department), genomic analysis (John Porter, Ph.D., in the neurology department), eye movement control (John Stahl, M.D., Ph.D., in the neurology department) to the question of understanding myasthenia gravis (Kaminski) and drug development (Charles Hoppel, M.D., in the pharmacology department) for the disease. Medof already has developed complement inhibitors, and during the first three years of the grant, the researchers will test several ways to adapt these inhibitors to precisely target the nerve-muscle communication points. In the last two years of the study, they will test their lead drug for safety.

As part of their work, Porter will use sophisticated DNA analysis to evaluate precisely how muscles are affected on the genetic level by myasthenia gravis. He will use DNA microarray analysis, which can identify nearly all genes functioning (or expressed) in a tissue. 'This can tell us how skeletal muscles are responding to the injury caused by myasthenia gravis. Such methods often provide unexpected results that lead to unique insights into how a disease is caused,' said Kaminski.

Another feature of this study is the comprehensive study of eye muscle involvement. The researchers will evaluate how eye muscles are affected by the disease and in particular if the drug or drugs the researchers develop can protect these muscles from the disease. 'This has never been done before,' said Kaminski.

Dennis Landis, M.D., chair of the Department of Neurology, said, 'This successful grant application proceeded from a remarkable multidisciplinary cooperation, bridging several academic departments at University Hospitals of Cleveland and the Case School of Medicine.'

Jonathan Lass, M.D., chair of the Department of Ophthalmology and director of the Visual Sciences Research Center at Case and UHC, said, 'The people who suffer from this disease have crippling double vision and crippling drooping of the eyelids. A more targeted approach for treating the disease as Dr. Kaminski and his colleagues have proposed is very appealing to solve this problem. This truly represents the type of work the Case Research Institute is trying to foster, which is to bring fundamental discoveries from the laboratory to treat patients.'
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