April 2, 1997
Researchers at Johns Hopkins and Guilford Pharmaceuticals Inc., have successfullymodified a group of established drugs to stimulate nerve growth without suppressing theimmune system.
The researchers say the development is a critical step toward using the newcompounds as treatments for a wide range of neurodegenerative diseases like Parkinson'sdisease or multiple sclerosis, or brain injuries from stroke or head trauma.
"We showed that these compounds can cause recovery of functions and behaviorspreviously lost to nerve damage in lab animals," says Solomon Snyder, M.D., Hopkinsdirector of neuroscience and principal author on the paper, which appears in this month'sNature Medicine.
"We believe this is the first demonstration through an orally administered treatment ofa significant regenerative effect on nerve cells without suppression of the immune system."
Immunosuppressive drugs like cyclosporin A and rapamycin were originallydeveloped to prevent a patient's immune system from rejecting an organ transplant. Whenresearchers looked for the compounds immunosuppressive drugs bind to in the body, theyfound 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 bindingcause changes inside the cell--make it less likely that an immune cell will proliferate, forexample."
Hopkins scientists discovered that brain cells have 10 to 50 times more immunophilinsthan immune cells and that immunophilins in the brain are linked to a variety of importantnerve cell functions, including the ability to regenerate lost branches of the cell and generatenew branches.
Immunosuppressive drugs bind to immunophilins; together, the two interact with aprotein called calcineurin to suppress the immune system. Researchers at Hopkins andGuilford, using new techniques from molecular biology and a field called combinatorialchemistry, attached chemical structures to the drugs that prevented them from binding tocalcineurin but did not affect their ability to attach to immunophilins.
Scientists at Hopkins and Guilford put the new drugs to the test alongside the originalimmunosuppressive drugs, first in studies of chicken nerve cells in the lab, and later in ratswhose 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 surroundingthe branch, which is critical to recovery of function," says Snyder.
Representatives from Guilford hope to begin clinical trials of some of the new drugs ina year or more. Guilford is a private biopharmaceutical company based in Baltimore.
Under an agreement between Johns Hopkins University and Guilford, Snyder and TedDawson, M.D., Ph.D., another Hopkins author on the Nature Medicine paper, are entitled to ashare of royalties received by the University from Guilford. The University owns stock inGuilford, with Snyder and Dawson having an interest in the University share under Universitypolicy. Snyder serves on the Board of Directors and the Scientific Advisory Board ofGuilford, is a consultant to the company, and owns additional equity in Guilford. Thisarrangement is being managed by the Johns Hopkins University in accordance with its conflictof 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 ofHopkins. The studies were funded by Guilford and the National Institutes of Health.
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