Researchers at Johns Hopkins and Guilford Pharmaceuticals Inc., have successfully modified a group of established drugs to stimulate nerve growth without suppressing the immune system.
The researchers say the development is a critical step toward using the new compounds as treatments for a wide range of neurodegenerative diseases like Parkinson's disease or multiple sclerosis, or brain injuries from stroke or head trauma.
"We showed that these compounds can cause recovery of functions and behaviors previously lost to nerve damage in lab animals," says Solomon Snyder, M.D., Hopkins director of neuroscience and principal author on the paper, which appears in this month's Nature Medicine.
"We believe this is the first demonstration through an orally administered treatment of a significant regenerative effect on nerve cells without suppression of the immune system." Immunosuppressive drugs like cyclosporin A and rapamycin were originally developed to prevent a patient's immune system from rejecting an organ transplant. When researchers looked for the compounds immunosuppressive drugs bind to in the body, they found a group of proteins called immunophilins.
"These are proteins frequently used by the cell for what we call signal transduction," explains Snyder. "They bind to something outside the cell, and as a result of that binding cause changes inside the cell--make it less likely that an immune cell will proliferate, for example."
Hopkins scientists discovered that brain cells have 10 to 50 times more immunophilins than immune cells and that immunophilins in the brain are linked to a variety of important nerve cell functions, including the ability to regenerate lost branches of the cell and generate new branches.
Immunosuppressive drugs bind to immunophilins; together, the two interact with a protein called calcineurin to suppress the immune system. Researchers at Hopkins and Guilford, using new techniques from molecular biology and a field called combinatorial chemistry, attached chemical structures to the drugs that prevented them from binding to calcineurin but did not affect their ability to attach to immunophilins.
Scientists at Hopkins and Guilford put the new drugs to the test alongside the original immunosuppressive drugs, first in studies of chicken nerve cells in the lab, and later in rats whose sciatic nerve had been crushed. There was no significant difference in the new drugs' ability to stimulate growth of new nerve cell branches and cause regeneration of lost branches.
"The new drugs were even able to regenerate the protective myelin sheath surrounding the branch, which is critical to recovery of function," says Snyder.
Representatives from Guilford hope to begin clinical trials of some of the new drugs in a year or more. Guilford is a private biopharmaceutical company based in Baltimore.
Under an agreement between Johns Hopkins University and Guilford, Snyder and Ted Dawson, M.D., Ph.D., another Hopkins author on the Nature Medicine paper, are entitled to a share of royalties received by the University from Guilford. The University owns stock in Guilford, with Snyder and Dawson having an interest in the University share under University policy. Snyder serves on the Board of Directors and the Scientific Advisory Board of Guilford, is a consultant to the company, and owns additional equity in Guilford. This arrangement is being managed by the Johns Hopkins University in accordance with its conflict of interest policies.
Other authors on the Nature Medicine paper were Joseph Steiner, Maureen Connolly, Greg Hamilton and Heather Valentine, of Guilford; and, Ted Dawson, and Lynda Hester of Hopkins. The studies were funded by Guilford and the National Institutes of Health.
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