WASHINGTON _ A discovery of the gene responsible for thedevastating loss of spinal nerves characteristic of spinal muscularatrophy (SMA) shows how wrong things can go when the body failsto prevent cells from dying. However, that discovery may one dayhelp prevent the devastating and irreparable brain damage that resultsfrom the lack of blood flow to the brain caused by heart attack orstroke.
Researchers from the University of Ottawa reported at the 26thAnnual Meeting of the Society for Neuroscience Tuesday that thisSMA-associated gene can protect neurons from the damaging effectsof interrupted blood flow to the brain.
"Basically, this work shows that we can find drugs that will preventneurons from dying during stroke," said George Robertson, of theUniversity of Ottawa. Robertson stressed that there is a lot of work tobe done, but he also said, "We now have the proof of concept."
The Ottawa group discovered that people who inherited SMA lackedthe gene neuronal apoptosis inhibitor protein (NIAP), and as a result,the neurons in their spinal cord died via the process of programmedcell death, or apoptosis. Because the gene acts to prevent apoptosis,the researchers began to speculate that overexpression of the proteincould prevent brain cell death caused by ischemia or the lack ofoxygen to the brain.
The researchers simulated global ischemia _ the type of oxygendeficit that a patient having a heart attack would experience _ ingerbils by cutting off blood flow to the animals brains for fiveminutes. This type of ischemia specifically kills neurons in the CA1region of the hippocampus which is vital for learning and memories.
Prior to the ischemia, however, the researchers injected a virusgenetically engineered to produce NAIP into this region of thehippocampus. The gerbils treated with this gene therapy not only hadincreased levels of NAIP in their brains, but they also experienced 60percent less neuronal death than their untreated counterparts.
"Up until a few years ago, brain damage from stroke was viewed assomething you could do nothing about," said Dennis Choi aneurologist with the University of Washington School of Medicine,in St. Louis, who also attend the meeting. "This work shows us thatwe can hope to prevent that brain damage from ever happening."
Gene therapy, however, is not likely to offer a feasible therapy forstroke patients when they enter the emergency room. A smallmolecule drug that can easily cross the blood-brain barrier and turnon the NAIP genes in the brains cells that are at risk is much moredesirable, noted Robertson.
"Much to our delight, we have found such a compound," saidRobertson. The Ottawa group discovered that the drug K252a, whichis a family of compounds produced by Cephalon, Inc. of WestChester, Pa., could increase the levels of NAIP in the brains ofgerbils. When tested, the drug prevented brain damage to thehippocampal neurons in the brains of oxygen deprived gerbils to thesame degree as the gene therapy.
The drug appears to work by turning off the gene that produces a keyenzyme on the apoptotic pathway. The researchers are still trying todiscover how that results in an increase in NAIP. Robertson notedthat "this compound has tremendous promise in the treatment ofstroke."
Cephalon is taking a derivative of K252a _ one of the compoundsthat they licensed from Kyowa Hakko Kogyo Ltd., in Japan, intoclinical trials to try to prevent the neuronal death found inAlzheimer's disease within the year. However, the company is alsolooking into possible therapies for stroke.
Robertson and Ottawa colleagues Robert Korneluk and AlexMacKenzie are so excited by the possibilities of treating strokevictims with a neuroprotective drug that they started their owncompany last year, Apoptogen Inc., in Ottawa, to try to find othermolecules that increase the levels of NAIP. n
-- Lisa Seachrist Washington Editor
(c) 1997 American Health Consultants. All rights reserved.