From the Robert Packard Center for ALS Research at Johns Hopkins

PACKARD CENTER GRANTEE TAKES ENCOURAGING STEPS TOWARD NERVE REGROWTH

Marie T. Filbin, Ph.D., is the Packard Center's latest grantee. A professor in the Department of Biological Sciences at Hunter College of the City University of New York, Filbin directs that institution's Specialized Neuroscience Research Program. She's won international recognition for her studies aimed at reversing paralysis --- work in which she found a key molecule, called MAG, in the insulating material, or myelin, that often ensheaths nerve cells. MAG inhibits nerve regrowth. Filbin's find has sparked something of a flurry of research directed at therapy, with potential both for repair of ALS-damaged tissue and that of other neuro-damaging illness.

Recently, a Packard Center writer asked questions about her work, as it relates to ALS.

RPC: Could you tell us generally what your research aims to do?

Dr. Filbin: Yes. We're trying to encourage damaged or degenerated nerves - both sensory and motor - to regrow. Of course, in ALS, it's motor neurons that are preferentially lost. We're exploring various approaches to try to recover nerve function, once you've halted the disease.

RPC: Isn't it a little early to be thinking about repair?

Dr. Filbin: Not really. Studies on what ALS does to cells are revealing more every day. It seems sensible to work in parallel to that. Then we'll be ready to step in when the disease is blocked. Also, there's always the chance that repair techniques we come up with might protect cells while the disease is still going on.

RPC: So what are you doing, exactly?

Dr. Filbin: We're trying to pave the way for replacement neurons. Work in a number of labs is looking at embryonic stem cells (ES cells) as a way to regrow neurons. But there's a basic problem in the brain and spinal cord. The way things are now, you could transplant ES cells into the spinal cord, for example. But they wouldn't grow out to muscles where they're needed.

RPC: Why not?

Dr. Filbin: We've known for some time that you can regrow or repair nerves in the body's periphery - in arms and legs, for example. Unfortunately, that's not so in the brain and spinal cord, where agents exist that inhibit nerve growth. It's part of a natural system to prevent overgrowth. We've been working to disable that system temporarily.

RPC: How?

Dr. Filbin: First, we had to identify the inhibitory agents. To date, we've identified three of them. Most of our work centers on one called myelin associated glycoprotein, or MAG. It's found within the protective, insulating material, myelin, that's wrapped around motor and some other nerve cells. If there's injury to those cells, myelin - with its MAG - hangs around and doesn't get cleared away. Then regrowing nerves encounter MAG, and when it binds to them, they stop growing.

RPC: Can you block MAG?

Dr. Filbin: That's one approach. You could, in theory, block MAG and the other neuron inhibitors with antibodies. But we think it might be simpler to change neurons from within, so they don't respond to the inhibitors. You change the "don't grow" message from within.

RPC: Have you had any success?

Dr. Filbin: Yes, in the laboratory. We found that a natural molecule, cyclic AMP (cAMP), acts like an over-ride for the "don't grow" pathway. If you elevate the amount of cAMP in neurons, they'll grow beautifully in laboratory cultures, even if the culture medium contains MAG.

RPC: So it would be useful to do this one day, perhaps, in patients?

Dr. Filbin: We're hoping that might be an approach. We've already found substances that can increase cAMP. One of the agents, given as a shot, can enter the brain or spinal cord and has already been FDA-approved for another purpose. So that's under investigation. We're also testing things in models of cell injury. So far, you get robust regrowth of neurons.

RPC: So does this look like the way to go?

Dr. Filbin: We're not sure. There may be better approaches than to increase cAMP which, after all, is a ubiquitous molecule in the body. You might get general effects elsewhere you didn't want. So we're trying to map out the "don't grow" pathway in neurons more precisely, trying to find more specific places downstream from cAMP to shut it off.

Also, we haven't seen how our methods to inhibit MAG's message will work around the embryonic stem cells that are being eyed for patients in the future. The work I'm doing that's supported by The Packard Center goes in that direction.

RPC: What does it involve?

Dr. Filbin: We're nudging ES cells to become motor neurons in culture to see how they respond to our different types of MAG-blockers. We'll see if the ES-derived motor neurons continue to grow outward as adult neurons would do when there's nothing stopping them. So far, our preliminary work looks good.

RPC: Will you just study cultures?

Dr. Filbin: No, we're starting to work with animal models of ALS and other injury models.

RPC: Anything else?

Dr. Filbin: We'd like to see if it's better to change the new neurons - the ones from the ES cells - from within. It's fairly easy to fine-tune genes in ES cells before they start turning into neurons. So instead of giving drugs or what-have-you to the animal, it might be easier to turn off the genes in the ES-grown nerve cells so they'll ignore growth inhibitors. It's a bit like wearing headphones to block the noise from a jet engine. We certainly think it's worth a try.

About The Robert Packard Center for ALS Research at Johns Hopkins

Located in Baltimore, the Robert Packard Center for ALS Research at Johns Hopkins is a collaboration of scientists worldwide, working aggressively to develop new treatments and a cure for amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease. The Center is the only institution of its kind dedicated solely to the disease. Its research is meant to translate from the laboratory bench to the clinic in record time.

Scientists and clinician members of the Center are unsurpassed at moving drugs reliably and rapidly from preclinical experiments to human trials. They're linked, directly or indirectly, to the world's major pharmaceutical and biotechnology companies, which have both infrastructure and experience to make promising drugs into therapies.

Center scientists are the first to propose and test a combination approach to drug therapy, a tactic that has worked for AIDS, cancer and other diseases.

ALS is a devastating, progressive neuromuscular disease that causes complete paralysis and loss of function - including the ability to eat, speak and breathe. ALS progresses quickly and is not curable. Most patients die within five years of diagnosis.

To learn more about The Robert Packard Center for ALS Research at Johns Hopkins, including information on its latest research and treatment, log on to www.alscenter.org

Recently, a Packard Center writer asked questions about her work, as it relates to ALS.

RPC: Could you tell us generally what your research aims to do?

Dr. Filbin: Yes. We're trying to encourage damaged or degenerated nerves - both sensory and motor - to regrow. Of course, in ALS, it's motor neurons that are preferentially lost. We're exploring various approaches to try to recover nerve function, once you've halted the disease.

RPC: Isn't it a little early to be thinking about repair?

Dr. Filbin: Not really. Studies on what ALS does to cells are revealing more every day. It seems sensible to work in parallel to that. Then we'll be ready to step in when the disease is blocked. Also, there's always the chance that repair techniques we come up with might protect cells while the disease is still going on.

RPC: So what are you doing, exactly?

Dr. Filbin: We're trying to pave the way for replacement neurons. Work in a number of labs is looking at embryonic stem cells (ES cells) as a way to regrow neurons. But there's a basic problem in the brain and spinal cord. The way things are now, you could transplant ES cells into the spinal cord, for example. But they wouldn't grow out to muscles where they're needed.

RPC: Why not?

Dr. Filbin: We've known for some time that you can regrow or repair nerves in the body's periphery - in arms and legs, for example. Unfortunately, that's not so in the brain and spinal cord, where agents exist that inhibit nerve growth. It's part of a natural system to prevent overgrowth. We've been working to disable that system temporarily.

RPC: How?

Dr. Filbin: First, we had to identify the inhibitory agents. To date, we've identified three of them. Most of our work centers on one called myelin associated glycoprotein, or MAG. It's found within the protective, insulating material, myelin, that's wrapped around motor and some other nerve cells. If there's injury to those cells, myelin - with its MAG - hangs around and doesn't get cleared away. Then regrowing nerves encounter MAG, and when it binds to them, they stop growing.

RPC: Can you block MAG?

Dr. Filbin: That's one approach. You could, in theory, block MAG and the other neuron inhibitors with antibodies. But we think it might be simpler to change neurons from within, so they don't respond to the inhibitors. You change the "don't grow" message from within.

RPC: Have you had any success?

Dr. Filbin: Yes, in the laboratory. We found that a natural molecule, cyclic AMP (cAMP), acts like an over-ride for the "don't grow" pathway. If you elevate the amount of cAMP in neurons, they'll grow beautifully in laboratory cultures, even if the culture medium contains MAG.

RPC: So it would be useful to do this one day, perhaps, in patients?

Dr. Filbin: We're hoping that might be an approach. We've already found substances that can increase cAMP. One of the agents, given as a shot, can enter the brain or spinal cord and has already been FDA-approved for another purpose. So that's under investigation. We're also testing things in models of cell injury. So far, you get robust regrowth of neurons.

RPC: So does this look like the way to go?

Dr. Filbin: We're not sure. There may be better approaches than to increase cAMP which, after all, is a ubiquitous molecule in the body. You might get general effects elsewhere you didn't want. So we're trying to map out the "don't grow" pathway in neurons more precisely, trying to find more specific places downstream from cAMP to shut it off.

Also, we haven't seen how our methods to inhibit MAG's message will work around the embryonic stem cells that are being eyed for patients in the future. The work I'm doing that's supported by The Packard Center goes in that direction.

RPC: What does it involve?

Dr. Filbin: We're nudging ES cells to become motor neurons in culture to see how they respond to our different types of MAG-blockers. We'll see if the ES-derived motor neurons continue to grow outward as adult neurons would do when there's nothing stopping them. So far, our preliminary work looks good.

RPC: Will you just study cultures?

Dr. Filbin: No, we're starting to work with animal models of ALS and other injury models.

RPC: Anything else?

Dr. Filbin: We'd like to see if it's better to change the new neurons - the ones from the ES cells - from within. It's fairly easy to fine-tune genes in ES cells before they start turning into neurons. So instead of giving drugs or what-have-you to the animal, it might be easier to turn off the genes in the ES-grown nerve cells so they'll ignore growth inhibitors. It's a bit like wearing headphones to block the noise from a jet engine. We certainly think it's worth a try.

About The Robert Packard Center for ALS Research at Johns Hopkins

Located in Baltimore, the Robert Packard Center for ALS Research at Johns Hopkins is a collaboration of scientists worldwide, working aggressively to develop new treatments and a cure for amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease. The Center is the only institution of its kind dedicated solely to the disease. Its research is meant to translate from the laboratory bench to the clinic in record time.

Scientists and clinician members of the Center are unsurpassed at moving drugs reliably and rapidly from preclinical experiments to human trials. They're linked, directly or indirectly, to the world's major pharmaceutical and biotechnology companies, which have both infrastructure and experience to make promising drugs into therapies.

Center scientists are the first to propose and test a combination approach to drug therapy, a tactic that has worked for AIDS, cancer and other diseases.

ALS is a devastating, progressive neuromuscular disease that causes complete paralysis and loss of function - including the ability to eat, speak and breathe. ALS progresses quickly and is not curable. Most patients die within five years of diagnosis.

To learn more about The Robert Packard Center for ALS Research at Johns Hopkins, including information on its latest research and treatment, log on to www.alscenter.org