Two researchers at Washington State University have developed a compound that they believe could help patients who suffer from early-stage Alzheimers disease and other forms of dementia.


Jay Wright, a psychologist, and Joe Harding, a biochemist with the universitys veterinary school, have been synthesizing and testing their compound, Norleu, a drug they say activates a receptor in the brain that facilitates cognitive processes. After 11 years of research including three years of animal studies, the scientists are hopeful that the drug could be manufactured for human use in as few as three years. Some pharmaceutical companies already have approached the researchers, who do their work with a small staff of students in Pullman through a company they have founded called Pacific Northwest Biotechnology Inc. (PNB).


Its a responsibility to us to take this technology that we have hope and faith in and find out if its useful, Wright says.


Four U.S. Food and Drug Administration-approved drugs are used to treat Alzheimers disease now, but they all work in a similar way thats distinctly different from how Norleu functions, Wright says. Those drugs enhance the action of acetylchlorine, a natural neurotransmitter that Alzheimers patients lack and that the disease degenerates. Norleu, on the other hand, activates whats called the angiotensin IV receptor, improving communication between neurons, he says. The drug also produces synapses, or gaps between neurons, that boost the health of cognitive functions.


What were doing is a totally different approach, Wright asserts. Were trying to facilitate communication in neurons that are healthy rather than focusing on a neurotransmitter that is diminishing.


About 75 percent of Alzheimers patients show no improvement from the drugs available now, Wright says, and the disease remains a major health concern.


Studies show that it occurs in about 10 percent of the over-65 population in the U.S., Canada, and other developed countries, and about 50 percent of people who are over age 85 will show signs of the disease, Wright says. Norleu shows promise in treating those patients, as well as victims of stroke and acute brain trauma, of which there are about 2 million survivors annually, he says.


The cost of treating Alzheimers and stroke patients in this country is estimated at about $87 billion a year, and as baby boomers age, the number of people suffering from neurodegenerative diseases, such as Alzheimers, is expected to increase markedly, he says. If further trials of Norleu go well, the drug potentially could tap into that huge market and be a commonly used treatment for those patients, he says.


Norleus potential initially is to treat stage I and stage II Alzheimers, which are the diseases earlier progressions. It doesnt appear that it will help late-stage Alzheimers, nor does it sharpen the memory of normally functioning brains, Wright says.


More research must be done, though, before the drug can be used in trials with human patients.


The research


The work began in 1992, when Wright and Harding discovered the previously unrecognized receptor. They found it mostly in the hippocampus and neocortex of the brain, where long-term memory is formed and retrieved.


Eli Lilly & Co., a large Indianapolis-based pharmaceutical company that has some operations here, pumped $800,000 into the research, helping the scientists discover the receptors function.


Once Wright and Harding determined that function, they began developing compounds to interact with the receptors, ending up with more than 300 such compounds. Some inhibited memory, they say, and others enhanced it.


Wright, who originally had set out to discover a brain receptor linked to hypertension, had to study memory and learning for the first time in his career.


When people think of psychologists, they either think of Bob Newhart or people in little white coats with rats, he says, but I had never really worked with mazes.


He says it took a year, but he and Harding figured out how to test Norleu and the other compounds using lab rats. While traditional rat mazes employ food deprivation to motivate the test subjects, the scientists couldnt tinker with the rats food intake because doing so would have interfered with the drugs interaction with the receptors. Instead, they used another form of motivation: water. Although rats are adept at swimming, they hate to do it, Wright says.


Wright and Harding built a sort of swimming pool for the animals out of a 6-foot diameter vat. It is a few feet deep and is painted black inside to hide a small pedestal from the rats vision. The pool is surrounded by four walls, each with its own visual clues on it, such as squares, triangles, and circles. The scientists keep the surroundings consistent, so that the rats can learn to associate the visual clues with the location of the pedestal.


The scientists altered the rats brains, either surgically or with chemicals, reducing their memory capacity by an estimated 65 percent.


By doing that, were approximating what would happen with Alzheimers patients, Wright says. Were trying to compromise the animals ability to solve the maze, then we give Norleu to them to try to facilitate the process of finding the pedestal.


Research also has been done to simulate other forms of dementia, such as in stroke victims, but PNBs main focus of study so far has been with Alzheimers, Wright says.


In the trials, the scientists found that Norleu significantly helped rats remember the location of the pedestal. Rats with altered memories took almost two minutes at first to find it. Over a period of eight days, the rats treated with Norleu were able to find the pedestal in about 20 seconds, while the rats that werent given the drug still took at least a minute to find it.


Over the testing period, rats that had not had their memories altered in the first place had a similar ability to find the pedestal as the Norleu-treated rats.


That means Norleu is working pretty well for us, Wright says.


PNB has been conducting such tests for about five or six years, but to follow the FDAs protocol for drug approval, more studies must be done.


The memory effects of Norleu also are being tested in rats at a lab in Australia, while other universities are testing the memory effects of compounds made at those universities with Wright and Hardings direction. They dont call those compounds Norleu because they didnt ship those institutions their drug.


The next stage is to test Norleus toxicological effects on another animal species, such as dogs or monkeys. Such tests would be done to determine potential side effects of the drug. In the rats, thus far, PNB hasnt found any negative side effects, Wright says. The toxicological tests can take six months to a year and cost about $1 million, he says.


If those stages of testing are successful, two sets of human clinical trials must be completed under guidance from the FDA. The first human trial probably would include about six to 12 Alzheimers patients, and the second would involve several hundred patients and could cost between $1 million and $2 million, Wright estimates.


PNB has submitted an application for a small-business innovation research grant to the National Institutes of Health (NIH) to finance the toxicity trials and the first phase of the clinical trials, he says. Nigel Davey, associate director of the Spokane Intercollegiate Research and Technology Institute (SIRTI), which recently began serving as an adviser to PNB, says he believes that grant request is for $800,000. The NIH previously granted PNB $140,000 for the project.


SIRTI featured PNB at a technology showcase event held April 2. The two entities dont have a formal relationship now, but Davey hopes to formalize a partnership of some sort soon. He also says a venture capitalist from outside of the Eastern Washington area was scheduled to visit PNB last weekend, but he declines to name that person or company.


PNB doesnt know yet whether Norleu would be administered as a pill, an injection, or through some other means. To develop a pill, which is the ideal objective, the drug would have to be resistant to the gastrointestinal tract and be absorbable into the bloodstream. It also would have to break through the blood-brain barrier, Wright says, referring to the semipermeable membranes that protect the brain from some substances. All of those are challenges that PNBs research hasnt addressed.


Its a long struggle, he says. Its expensive, too.


Thats why PNB could be tempted to sell its research to a pharmaceutical company, Wright says. Doing so would mean PNB would no longer be involved in the study, development, or possible manufacturing of Norleu.


Our plan right now is to take it a little further, to take it through toxicological trials, he says. It is our baby and we feel territorial about it.


Its a gamble, though. If PNB foots the bill for further studies only to find that Norleu either is ineffective or has dangerous side effects, the small company would have lost millions of dollars of research, and Wright and Harding would have lost years of time and energy.


Although other pharmaceutical companies have approached PNB, Wright says his preference would be to sell the research to Eli Lilly, the company that showed faith in the idea a decade ago. He declines to disclose the other companies that have approached PNB. He also declines to estimate how much he believes a pharmaceutical company would pay PNB for the research.


Wright says, though, that Norleus potential to help people that motivates him and Harding to continue their work. The research has consumed the scientists since 1992, and Wright says they feel a responsibility to the public to determine whether Norleu could help Alzheimers sufferers.


Researchers always have hopes, he says. To find an answer is the top priority of what we do.