Tuesday, June 21, 2005

Purdue Scientists May Have Found Key to Halting Spinal Cord Damage

WEST LAFAYETTE, Ind., June 21 (AScribe Newswire) -- Purdue University researchers may have isolated the substance most responsible for the tissue damage that follows initial spinal cord injury, a discovery that could also improve treatments for a host of other neurodegenerative conditions.

A research team led by Riyi Shi (REE-yee SHEE) has found that a chemical called acrolein, a known carcinogen, is present at high levels in spinal tissue for several days after a traumatic injury. Although acrolein is produced by the body and is non-toxic at normally occurring low levels, it becomes hazardous when its concentration increases, as it often does in tissue that experiences stresses such as exposure to smoke or pesticides. That list of stresses now includes physical damage, and in the case of spinal injury, acrolein's hazard may be the key in causing debilitating paralysis that sets in after the initial trauma.

"When a spinal cord ruptures, not only are the traumatized cells at increased risk of damage from free radicals that oxidize the tissue, but the cells also spill chemicals that actually help the free radicals to launch repeated attacks," said Shi, who is an associate professor of neuroscience and biomedical engineering in Purdue's School of Veterinary Medicine and Weldon School of Biomedical Engineering. "Our latest research indicates that acrolein may be the primary culprit that enables this vicious cycle. Because acrolein has already been implicated in cancer and neurological diseases, drugs that detoxify it could become important for treating not only spinal cord damage but a host of other conditions as well."

The research, which Shi carried out with his student Jian Luo and Koji Uchida of Japan's Nagoya University, appears in the now-available March 2005 issue of the scientific journal Neurochemical Research.

Free radical molecules are well-known enemies of bodily health, and for years, physicians have recommended a diet rich in antioxidants - such as vitamins C and E - which are able to attach themselves to free radicals, detoxifying them. While there is nothing inherently wrong with this approach, Shi said, it might not be getting at the root of some health problems.

"Antioxidants are good scavengers of free radicals, and it's certainly wise to have plenty of them circulating in your bloodstream," he said. "The trouble is that when free radicals start attacking tissue, it happens in a tiny fraction of a second, after which they are gone. But the acrolein that these attacks release survives in our bodies much longer, for several days at least, and its toxicity is well documented."

For example, acrolein has long been known to cause cancer when its concentration in the body rises, and not much is needed to be dangerous. When a person inhales smog or tobacco smoke, for example, the fluids lining the respiratory tract show an acrolein concentration of about a millimole - not much by measuring-cup standards, but still over 1,000 times more than usual.

"If you took a single grain of salt from a shaker and dissolved it in a liter jug, the water wouldn't taste very salty," Shi said. "But even that would be more than a millimole, and that's much more acrolein than the body can handle at once."

Because a high concentration of acrolein also has been linked to neurodegenerative conditions such as Parkinson's, Huntington's and Alzheimer's diseases - all of which progress slowly and resist treatment - Shi's team decided to see if the chemical was present in another slow-developing, seemingly untreatable condition: the degeneration of the spinal cord after initial traumatic injury.

"Unlike most other parts of the body, spinal cord tissue does not heal after injury," Shi said. "After the initial shock, it actually gets worse. Science has long been aware that some chemicals the damaged cells release are part of the problem, but no one has ever been sure which chemicals are responsible."

When a spine is damaged, the change in its ability to function follows a well-defined pattern. In response to the initial shock, the spine immediately becomes completely nonfunctional but then starts to recover quickly. Over the course of the next few days, in response to the secondary damage, the spine's function again begins to drop, and within about three days it has leveled off at a point of near non-functionality.

"What our group did was measure the levels of acrolein in the injured spines of 25 guinea pigs for several days following an injury," Shi said. "We found that levels of acrolein peak 24 hours afterward, and they remain high for at least a week. Because acrolein has such a long lifespan and is so toxic, we theorize that it is primarily responsible for the secondary damage that keeps injured spines from healing."

Acrolein's involvement with other conditions suggests that it could be the key to fighting a number of diseases, Shi said.

"When the brain suffers a stroke, for example, it is deprived of oxygen, which is often thought to be the cause of brain damage. But, in fact, you can starve the nervous tissue of oxygen for up to an hour without harm if only you control the acrolein levels," Shi said. "This paper suggests that the body is generally pretty resilient but that acrolein may be something it can't handle."

Shi said that some drugs already under development for other conditions could be used to treat neurodegenerative diseases as well.

"Hypertension drugs, which bind to acrolein and detoxify it, are already under study for their added potential to promote liver health," Shi said. "We would like to see whether they also could be modified to treat the conditions we are interested in."

Further research will be necessary to determine how great a role acrolein actually plays in the process of secondary spinal cord damage, but Shi said that once this role is clarified, drugs that counter acrolein's effects could join the other approaches to treating spinal cord injury under development at Purdue's Center for Paralysis Research.

"My colleague Richard Borgens and I have already had our hands in developing PEG, a substance that coats damaged spinal cells so that their membranes can heal and also oscillating field stimulator implants that encourage the tissue to regenerate," Shi said. "We are hopeful that detoxifying acrolein will allow doctors to stop the chemical attack cycle as well, adding to the number of treatment methods available."

The center was established in 1987 both to develop and to test promising methods of treatment for spinal cord injuries. The center uses its close affiliation with the Department of Veterinary Clinical Sciences in the College of Veterinary Medicine to move basic laboratory methods into clinically meaningful veterinary testing.

This research was funded in part by the National Institutes of Health and the State of Indiana.
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Wednesday, June 15, 2005

Free Brochure for Spinal Cord Injury Prevention

The United Spinal Association is offering free copies of "Stay Safe", an online booklet focusing on prevention of a traumatic spinal injury. The booklet also contains brief, basic information on the nature of a spinal cord injury, as well as additional Website prevention resources. Each year, there are approximately 11,000 new spinal cord injuries in the United States. You can download "Stay Safe" in either text or PDF format at the United Spinal Association website.
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Wednesday, June 08, 2005

Dr. Wise Young - Interview

COVER STORY: 'We have to overcome this hope barrier'


Ten minutes after a recent announcement that South Korean scientists had discovered an efficient way to produce stem cells, the world's largest spinal cord Web site carried the story.

"It's unbelievable someone's trolling the literature and posting it right away like that," said Dr. Wise Young, administrator of www.sciwire.com.

Young, a Rutgers University neuroscientist, began the Web site in July 2001. He spends up to eight hours a day administering it, often signing off at 3 a.m., he says. He is both scientist and ombudsman to its 10,000 registered members.

A huge area of interest is cellular therapies abroad, particularly procedures in Portugal and China. They remain controversial because their results are largely unpublished. The therapies are costly, ranging from $20,000 to $50,000, and they hold risks. For now, Young's site is one of the sources patients turn to for updates on how patients fare after the surgery.

Young, 55, born in Hong Kong and raised there and in Japan, was the late actor Christopher Reeve's doctor. He helped lead a landmark 1990 study that became the standard of care for the immediate treatment of spinal cord injuries. It found that high-doses of methylprednisolone, a steroid drug, saved about 20 percent of motor and sensory function when administered soon after a spinal cord injury.

The study "was the beginning of my radicalization" because it took so long to convince medical centers to stock and administer the drug, Young says. Their reaction was like "cold water being thrown on my face."

More recently, Young has been involved with a new drug, Fampridine-SR, or 4AP (which stands for 4-aminopyridine). It "helps boost the firing of neurons" after a spinal cord injury, he says. The drug, made by Acorda Therapeutics, plugs potassium channels that leak into nearby nerve cells, causing them to short-circuit. Closing the channels lets the nerve cells transmit impulses again. Young is on the company's board of directors.

He is married with two grown children and is professor and chair of the Department of Cell Biology and Neuroscience at Rutgers in New Jersey. He obtained his medical degree from Stanford University in Palo Alto, Calif., and his doctorate in physiology and biophysics from the University of Iowa.

Young was in Ypsilanti in late April to address Connection to SCI Cure, an all-day symposium sponsored by the University of Michigan. The following are excerpts from a one-hour interview that followed his keynote speech.

QUESTION: People are literally champing at the bit to find out when clinical trials with some of the stem cell therapies will begin in the United States. What kind of timetable do you envision?

ANSWER: Embryonic stem cells will take a while. There are two major problems that need to be solved with embryonic stem cells. One is we need very good screens (tests) to find the possibility of cancer. Those things are not yet available. Although other countries might be more willing to take risks of that nature, in the United States that would be less acceptable. I think this will produce a delay. The FDA (Food and Drug Administration) will want extensive safety data. It will have to be collected.

The problem is we haven't had the cells to work with to collect that data. And even with the 22 cell lines we do have (embryonic cell lines President George W. Bush approved for use), the work is really slow. I'm expecting New Jersey and California to be putting resources into this. These resources (from states) already exceed the federal resources (in stem cell research). I'm hopeful we'll see a picking up of the research that will solve that one major problem: getting an effective, reliable screening test.

All the so-called human embryonic stem cell groups are specializing in the study of existing stem cell lines. They are not creating new cell lines. So whatever clinical trial goes on, you need a center capable of producing new lines. There may be a dozen states with centers established. It will be two to three years before these centers are up and going and are well staffed.

Q: Do you find much collaboration or the opposite: turf wars?

A: Scientists collaborate. The worst battles I've seen in science are over two issues: credit and money. Every reporter I've talked to has asked me: Will this stuff be shared, and are these state programs bad for sharing? I don't see this at all. In California, there are 30 institutions vying for the same pot of money. I can guarantee you there's more competition there than there is between New Jersey and California. We can help them. They welcome this offer. The competition isn't there. There aren't enough of us to compete.

Q: What do you think will happen in New Jersey?

A: We have a very strongly committed (acting) governor. Richard Codey has committed $150 million in state funds to build a stem cell research center. We're also trying to get a referendum on the ballot for November to determine whether the state should issue bonds to finance grants for stem cell research. There may not be enough votes in the assembly to pass the referendum, so all the advocacy groups are clustering around Trenton.

The pro-life groups and the Catholic Church and a couple of other groups have basically seen New Jersey as the battleground where they draw the line. If New Jersey falls, they see all the other states doing the same. So they are pouring troops and money to stop the referendum. Politics is politics. It's who speaks louder.

Q: Tell us what you know about China and the work being done with olfactory ensheathing glial cells (OEGs) by Dr. Hongyun Huang. (OEGs are not stem cells, but cells from the olfactory bulb used in cell therapy. The cells have protective properties that help shore up nerve growth and connections.)

During your talk you called OEGs a "naturally migrating cell" capable of forming protective myelin sheathing over nerve cells. You mentioned that you've heard of three deaths out of some 500 or more procedures. What do you know about them?

A. I was referring to deaths in spinal cord patients. There may be as many as 10 in ALS (amyotrophic lateral sclerosis) patients, but I don't know that for sure.

Q: What might distinguish people who respond to this therapy from those who don't?

A: I've been trying to tell people not to expect miracles. Dr. Huang is not matching (blood types of donors to transplant recipients). He just schedules the surgery around getting the cells from fetuses. It's not possible to match, or it's very difficult. Your chances of finding a match are 1 in 10,000, so Dr. H doesn't want to waste any time finding a match. When they become available, he transplants them. It is said, but nobody knows for sure, that there are stem cells inside. You can't tell. We don't know what portion of cells is rejected. The data suggest patients are getting some early recovery and then they stabilize or plateau. After several months, very few patients continue to get better.

Q: Are these patients getting aggressive rehabilitation afterward to maximize any benefits of the surgery?

A: It's extremely variable. Most don't have supervised physical therapy. And there's a real change in attitude when you go there. They are highly motivated. Motivation makes a difference.

Q: Do you agree with the patient who spoke today about having gone to China and having talked to people who went there, and half said they've improved and half have not? And what about the other speaker who said he's gotten very little benefit beyond breathing better?

A: In my presentation, I showed the results of 171 patients (from a study published by Huang in a Chinese journal). There was an average improvement in one or two muscles, not great, and in 13 to 25 sensory points. In older patients, it was 24 points. So the sensory response is quite consistent. The question is: Is it worthwhile to go through this thing just to get feelings in your chest back? I can say the motor response, on average, is one level. Is that worthwhile? That's the average response. Some people get less and some people get more.

Q: Does age or anything else affect response to the surgery there?

A: I see no difference in response and time after injury, age or sex (of the patient). However, there are relatively few women (going to China). Eighty percent are men. There's just not enough data to say.

Q: You have expressed reservations about spinal autograft surgery in Portugal as well.

A: I'm just saying I'm not convinced any gains are from stem cells or OEG cells. The Lisbon team transplanted the patient's own nasal mucosa into the spinal cord. It contains many cell types, including possibly stem cells and OEG cells, but it's not clear that either of these cell types survive the transplantation or contribute to the recovery of patients.

It's important to continue this research, and I support this research. I do have difficulty with two things, and I've said this publicly. I have difficulty with the fact that they take out a piece of spinal cord when they operate. That may cause more scar tissue. I asked Carlos (Dr. Carlos Lima, the spokesman for the Lisbon team): "Why do you take out a piece of the spinal cord?" And he says: "To remove scar tissue." And I follow up and say: "How do you know it's scar tissue?" He says: "We know." He showed samples of tissue he removed, and there are axons in it. Axons are nerve fibers in the spinal cord that conduct impulses. The presence of axons in removed spinal cord samples suggests the team removed some nerve fibers from the spinal cord.

I think it's OK to say we're going to do this in complete patients, people who have no sensation below the injury. Those patients don't have that much to lose. Another thing is we are not seeing the data from all his patients.

Q: Dr. Lima said in early May he has performed the surgery on 52 patients and that all have improved, though four developed temporary problems or loss of sensation.

A: He says they all have improved. But he doesn't do the standard exam, and he's not a spinal cord injury doctor. I'm aghast at the fact that he thinks he can remove parts of the spinal cord. I also asked him about deaths. He says there are none. I also have been told the neurosurgeon (Dr. Pratas Vital) doing the operation is very good. I respect that. But I've been urging everybody before they go to Portugal to ask these critical questions.

I talked to four or five people who went to Portugal and who post regularly (on sciwire). One young man says he's gotten a lot of sensation back and some function back. I hesitate to challenge him. It's clear he's very committed to getting better. I tell people to ask the doctors how much tissue will you remove and what is the criterion by which you will remove the tissue?

Q: You were Christopher Reeve's doctor. You've mentioned how he taught you not to be afraid of using the word "cure." How much did he contribute to your philosophy?

A: "Cure" isn't a word that comes easily to a scientist. You don't want to be promising something you can't deliver. What Christopher convinced me about is that the main problem is hope. We don't have hope. We have to overcome this hope barrier.

The new barrier is money. I've started to use the word "billions." That's what we need. People gasp when they hear it. We've set our sights so low that we would have been ecstatic if they gave us another $100 million. In the meantime, look at AIDS. George Bush, in the middle of the worst deficit, last year committed $10 billion to AIDS in Africa. It's not like you can't ask for it and you can't get it.

Q: What is the Spinal Cord Injury Network you are trying to begin in Asia?

A: We're forming a clinical trials network. We will be collaborating in controlled clinical trials and hope to begin in 2006.

Q: Will the studies test a range of cellular therapies?

A: Yes. In China, there's no possibility of doing placebo-controlled trials (a study in which one group gets a treatment and the other a placebo or sugar pill). If you announce one, people say they don't want to participate. Also, we're been told sham surgery (faking an operation for the purpose of having a comparison group in a study) is illegal there. They think it's unethical. So the only thing we can do is compare bone marrow stem cells to OEG cells. That's legitimate.

All the evidence today suggests that cell transplants alone do just a little bit. But if you add human growth factors or growth inhibitors you get much better results. So all the patients will get one or another cell transplant, and then we will randomize them in addition to one or two other possibilities.

Q: What do you anticipate will be the cost of the trials network?

A: The first year, to set up the infrastructure, will be about $2 million.

Q: Will U.S. patients be eligible?

A: That's not up to me; it's up to the Chinese.

Q: You are organizing a first international spinal cord symposium in Hong Kong. Tell me about it.

A: Yes, it will be held Dec. 17-20 in Hong Kong. We hope to invite 300 researchers and another 300 Chinese for a four-day meeting. At the end of the meeting, I'd hope we will have a ranking of our priorities.
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