Amyotrophic lateral sclerosis (ALS), also called Lou Gehrig's disease, is a progressive, fatal neurological disease affecting as many as 20,000 Americans with 5,000 new cases occurring in the United States each year. The disorder belongs to a class of disorders known as motor neuron diseases.

ALS occurs when specific nerve cells in the brain and spinal cord that control voluntary movement gradually degenerate. The loss of these motor neurons causes the muscles under their control to weaken and waste away, leading to paralysis. ALS manifests itself in different ways, depending on which muscles weaken first.

Symptoms may include tripping and falling, loss of motor control in hands and arms, difficulty speaking, swallowing and/or breathing, persistent fatigue, and twitching and cramping, sometimes quite severely. ALS strikes in mid-life. Men are about one-and-a-half times more likely to have the disease as women.

There is no cure for ALS; nor is there a proven therapy that will prevent or reverse the course of the disorder. The Food and Drug Administration (FDA) recently approved riluzole, the first drug that has been shown to prolong the survival of ALS patients. Patients may also receive supportive treatments that address some of their symptoms.

ALS is usually fatal within three to five years after diagnosis.

Researchers make stem cell breakthrough

For years, scientists have dreamed of using stem cells to replace neurons damaged by brain or spinal cord injury or such neurological disorders as Parkinson disease, Alzheimer disease or amyotrophic lateral sclerosis (ALS).

But a major obstacle has always stood in the path of making such a therapy work: Whether derived from embryonic or adult tissue, only a few stem cells transform themselves into neurons when placed in most
areas of the brain and spinal cord. Most simply fail to de-velop, or become glial support cells, not the neurons that need to be replaced.

Now, in a breakthrough with great significance for the use of stem cells in central nervous system therapies, researchers at the University of Texas Medical Branch at Galveston (UTMB) have found a way to make
the majority of human fetal stem cells implanted into rat brains and spinal cords develop into neurons.

A Nature Neuroscience paper entitled "Region-specific gen-eration of cholinergic neurons from fetal human neural stem cells grafted in adult rat" (pub-lished in the journal's December issue) describes experiments by Ping Wu, Yevgeniya Ta-rasenko, Yanping Gu, Li-Yen Huang, Richard Coggeshall and Yongjia Yu in which they pre-treated human fetal stem cells with a mixture of chemicals im-portant to neuron development. When injected into the prefron-tal cortex, medial septum and spinal cord of adult rats - all "non-neurogenic" regions that normally do not produce new nerve cells - the "primed" cells almost all differentiated into neurons. Moreover, they devel-oped into exactly the right kind of neurons for the central nerv-ous system area into which they were implanted.

"This priming seems to get the cells into a plastic intermediate stage, and then after they're in-jected they acquire environ-mental cues and become spe-cific kinds of neurons according to where they're located," said Wu, an assistant professor of anatomy and neurosciences at UTMB.

Wu, who holds a doctorate in neuroendocrinology from UTMB in addition to a medical degree, has worked for 2 years to find a way to get fetal stem cells to develop into cholinergic motor neurons - nerve cells that release the neurotransmitter acetylcholine and also provide the link between the central nervous system and the mus-cles.

"As an MD, my ultimate goal is to find a way to help patients with neurological disorders and brain and spinal cord injury, and cholinergic neurons are what degenerate in disorders like Alzheimer's and Lou Gehrig's disease, as well as being dam-aged in spinal and brain trauma," Wu said. "Until now, nobody's been able to get a sig-nificant number of cholinergic neurons from primarily cultured stem cells, but using this primer we can get over 55% such neu-rons with transplanted stem cells."

Funded by a new researcher grant from the Sealy & Smith Foundation and a grant from The Institute for Rehabilitation and Research (TIRR) Mission Connect project, Wu's group is continuing to investigate the
possibilities for stem cell im-plantation - extending the stud-ies it has already conducted on healthy rats to those with spinal cord injury and motor neuron disease.

"We will see if we can produce the same results in those dis-eased animals, and then the next challenge will be to see if the neurons can actually make the right contact to the right targets - for example, if motor neurons are transplanted into the spinal cord, whether they can send fi-bers, or axons, to muscle," Wu said. "Then we'll see if they can release the neurotransmitters, and then look at function to
see if there is a long-term func-tional recovery.

"We also need to confirm that there is no tumor formation from the implanted stem cells. Then we're talking about real clinical significance and real clinical trials. And hopefully after we sort out those critical issues, we can think about clini-cal applications to treat neuro-degenerative diseases and spinal and brain trauma."

Source: The MDA/ALS Newsletter, September 2002

Gene Identification Project Underway for Lou Gehrig's Disease

Calabasas Hills, CA - The ALS Association (ALSA) has announced it has embarked on an unprecedented effort to identify new genes linked to familial ALS, applying the same technology as that used in the Human Genome Project and involving renowned leaders in genome and ALS research. The ALS Association is committing a minimum $1.5 million to this Gene Identification Project.

"The discovery of more genes linked to ALS is crucial for our understanding of disease mechanisms and may provide new targets for therapy, " said Lucie Bruijn, PhD, Science Di-rector and Vice President of The ALS Association. She points out that the discovery of several genes in familial Alz-heimer's disease all involved a common pathway, which has enabled the pharmaceutical in-dustry to focus on this pathway to develop therapies.

Traditionally, geneticists use the "candidate gene approach" to finding new disease-linked genes. In an attempt to dramati-cally hasten the gene identification process, this collaborative effort will capitalize on the advances in sequencing technology to rapidly sequence large regions of the chromosome linked to familial ALS. If successful this approach will have major implications on the iden-tification of gene mutations in other diseases.

"Using the same technology as that used in the Human Genome Project enables us to more sys-tematically and rapidly se-quence through large regions of the genome to identify genes linked to disease, It's more effi-cient and cost effective," says Dr. Eric Lander, director of the Whitehead Institute Center for Genome Research, who will spearhead this effort. "Also, using genomic DNA from ALS patients is the most direct and reliable way to identify ALS-linked genes."

The discovery of the Cu/Zn su-peroxide dismutase 1 (SOD1) gene on chromosome 21 linked to 20% of familial ALS (FALS), almost a decade ago made a major impact on ALS research. The development of an animal model, now the stan-dard for testing possible thera-pies for ALS, enabled scientists to begin to test a variety of dis-ease hypotheses. ALSA was a major contributor in the initial discovery and has funded many of the follow-up research stud-ies to date. Yet, genes linked to the remaining 80 percent of fa-milial ALS remain unknown.

Adds Bruijn, "The discovery of new disease-linked genes will provide important information in understanding not only the mechanisms of cell death in familial ALS, but also sporadic ALS which accounts for 90 percent of all ALS cases."

Dr. Robert Brown of the Mas-sachusetts General Hospital concurs, saying "There is no doubt that discovery of new causes of familial ALS will il-luminate our understanding of non-familial ALS. It is even possible that the new insights will be relevant to other brain degeneration diseases. This ini-tiative will ultimately be im-portant in devising new ways to treat ALS."

The participants in this project include Dr. Robert H. Brown, Jr., of Massachusetts General Hospital, Dr. Guy Rouleau of Montreal General Hospital, Dr. Jackie de Belleroche of Imperial College, Charring Cross Hos-pital, London, England, and Dr. Teepu Siddique of Northwest-ern University, who will con-tribute family resources. Dr. Pieter J. de Jong of the Chil-dren's Hospital Oakland Re-search Institute, will generate BAC libraries from FALS hy-brid cell lines prepared for each of the families through GMP Companies, Inc., and Dr. Eric Lander of the Whitehead Insti-tute Center for Genome Re-search, will direct the sequenc-ing of the selected BAC clones from these libraries.

"This international collabora-tion to identify new genes linked to familial ALS is among the most exciting and poten-tially informative projects we have initiated", says Dr. Tom Maniatis, head of ALSA's Cure ALS Advisory Committee. "We are very fortunate to have the outstanding geneticists who have identified new ALS loci working closely with scientists who played central roles in se-quencing the human genome. If successful, this effort will not only identify ALS genes associ-ated with currently identified familial loci, but will advance the technology required to identify additional ALS genes in the future."

Source: The MDA/ALS Newsletter, October 2002

Researchers Probe Role of Lipid Overload:

High levels of two kinds of lipids (fatlike substances) have been found in the spinal cord motor neurons of people with ALS and of mice with ALS, says a study published August 22 in the online edition of Annals of Neurology. The high lipid levels could contribute to cell death in ALS, through oxidative stress, a known contributor to cell death in ALS that involves the actions of metabolic byproducts called free radicals, as well as other possible mechanisms. The excess accumulation of ceramides and cholesterol esters occurs because of oxidative stress and then appears in turn to increase oxidative stress, leading to a vicious cycle in which cells die. When the investigators blocked lipid formation in laboratory containers with a chemical called ISP-1, they were able to save motor neurons. Mattson and colleagues are investigating the effects of blocking lipid formation.

Source: The MDA/ALS Newsletter, September 2002

A New and Improved Neurotrophic Factor?

Although many so-called neurotrophic factors have been tested and then shelved in clinical trials against ALS, a newcomer to the scene, called hepatocyte growth factor (HGF), might succeed where others failed, a Japanese research group says. GHF, a protein named for its ability to stimulate liver growth, turns out to have neurotrophic effects, meaning it can promote the growth and survival of nerve cells. In the August 1 issue of the Journal of Neuroscience, Toshikazu Nakamura and colleagues from Osaka University Graduate School of Medicine show that HGF delays paralysis and death in mice with ALS. The mice, which carry a mutant version of the SOD1 gene that causes familial ALS, died after about nine months without HGF. But mice given an HGF gene that's turned on at high levels in nerve cells lived an average of one month longer. Other neurotrophic factors have shown similar promise in mice, but then failed in humans with ALS. Nakamura and colleagues speculate that HGF might work better because it seems to act not only on the muscle controlling nerve cells killed by ALS, but also on astrocytes, a type of support cell in the nervous system. In nerve cells, HGF suppresses a protein that triggers cell death, and in astrocytes, it stabilizes EAAT2, a protein that normally cleans up toxic amounts of the brain chemical glutamate but somehow gets degraded in ALS.

Bile Acid's Nicer Side:

It's taken a bad rap through history, long associated with melancholy and jaundice, but bile acid could turn out to have therapeutic value against ALS and other neurological diseases. In the July 29 issue of the Proceedings of the National Academy of Sciences, Walter Low and colleagues from the University of Minnesota in Minneapolis show that injections of a type of bile acid, TUDCA, can stave off Huntington's disease in mice. TUDCA has antioxidant properties and also blocks "cell suicide,"or apoptosis, which is thought to be one way that nerve cells die an ALS. It's FDA-approved for the treatment of biliary cirrhosis, a liver disease. What's exciting about TUDCA, in addition to its remarkable anti-apoptotic quality, is that it's made by our own bodies (in the liver) and causes virtually no side effects when given as a drug. TUDCA may even have the potential for treating Parkinson's, Alzheimer's and ALS.

Scientists Find a Way to Turn Stem Cells into Motor Neurons:

Some researchers believe that stem cells - the primitive cells that assemble our bodies - have the potential to regenerate the muscle-controlling nerve cells (motor neurons) lost to ALS. A major obstacle to that approach: Scientists did not have an efficient way to make stem cells become motor neurons. But in the July 17 online edition of Cell, Thomas Jessell and colleagues at the Howard Hughes Medical Institute and Columbia University in New York report that they've done just that using mouse embryonic stem cells in a lab dish. They also show that the neurons, when implanted into mouse embryos, migrate to the right location in the spinal cord and make appropriate connections with muscle fibers. Skeptics say it would be a far greater - and perhaps impossible feat - for stem cells to replace and correctly "rewire" motor neurons in human adults, and that stem cells are more likely to work by producing growth factors or rebooting the immune system. Still, according to a Hughes Institute press release, Jessell plans to collaborate with other researchers to find out if his cells can restore function in mice with ALS. He also hopes to develop an efficient method of turning human embryonic stem cells into motor neurons.

Bone Marrow Transplanting in ALS:

During the Jerry Lewis MDA Labor Day Telethon, MDA funded researcher Stanley Appel announced that he and colleagues at Baylor College of Medicine in Houston have begun a clinical trial of bone marrow transplantation (BMT) for ALS. Appel, has performed BMT on six people with sporadic (nongenetic) form of ALS. It's too early to tell whether the treatment is working, but he's optimistic about the results.

Adult bone marrow contains stem cells that generate red blood cells and the white blood cells that make up the immune system. These blood-forming cells make BMT a powerful (though often last resort) treatment for certain blood disorders and immune deficiencies. Appel says there's a good chance that BMT will also work against ALS because recent studies, some them from his lab, suggest that the disease involves inflammation, with a possible attack of the immune system against the body's own tissues. BMT, in which the recipient's bone marrow is first destroyed, then replaced, could suppress the activated immune systems of people with ALS.

Since laboratory experiments have shown that bone marrow stem cells can be induced to form nerve cells, some researchers favor the idea of using BMT to actually replace dead nerve cells in ALS. In his trial, Appel is following standard BMT protocol, first giving the participants high-dose radiation and immunosuppressants, then giving them intravenous injections of bone marrow donated from an immonologically matched relative. Follow-up will last at least one year.

Source: The MDA/ALS Newsletter, August 2002

A New Creatine Product:

The Avicena Group of San Francisco says it has a creatine product that's much purer than what you can now buy over the counter, and that it plans to market the drug as a specific treatment for ALS. In February, Avicena received permission from the U.S. Food and Drug Administration to designate its creatine product, NEOtine, an "orphan drug." Orphan drugs are those developed to treat diseases affecting fewer than 200,000 people in the U.S. or those for which there's no reasonable expectation that development costs can be recovered from sales. NEOtine is being tested in a multicenter clinical trial in ALS. If the FDA is convinced that NEOtine is safe and effective in ALS and that it's sufficiently different from available creatine products, it could receive approval as an ALS treatment under the FDA's Orphan Products Program. Orphan drug designation is the first step toward final drug approval. The next step for us is to meet with the FDA in an investigational new drug meeting and decide the design of the final, phase 3 clinical trial (if one is needed) before applying for a new drug approval.

Minocycline:

Minocycline is an antibiotic that has been considered a potential neuroprotective agent for a while now. It may act at the level of the mitochondria (the energy producing units of cells.) Robert Friedlander at Harvard showed that it prolonged survival in mice with Huntington's disease, where many of the mechanisms of cell death seem to be similar to those in ALS. It's being given to patients with Huntington's disease in a pilot study at Harvard now. Minocycline has been shown to have benefit in models of Parkinson's disease and stroke, and now in models of ALS. It's been well tolerated in a small study in people with ALS that was conducted. There are now plans to greatly expand that study.

Source: MDA/ALS Newsletter, July 2002

Cord Blood, Banking on a Cure:

For people with ALS who are expectant parents or grandparents, the prospect of stem cell therapy has taken on practical significance, encouraged by preliminary studies suggesting that stem cells in human umbilical cord blood can fight against ALS. Now they are faced with the question of whether or not to bank the baby's cord blood now in hopes that it could cure ALS in the future.

Stem cells are primitive cells that can morph into specialized cell types-cells that many scientists believe have the potential to replace or repair the nerve cells lost to ALS. Embryonic stem cells, the movers and shakers of human development, form all of the tissues and organs in our bodies. Stem cells of more limited potential are abundant in adult bone marrow, where they replenish the constantly turned-over supply of blood cells.

Recent findings have shown that at least some stem cells in bone marrow have the capacity to form cells outside of the blood lineage, including nerve cells. So bone marrow stem cells- unfettered by the ethical and political complications of embryonic stem cells- are viewed by some as a potential fix-all for a host of diseases, including ALS. It turns out that the blood in the umbilical cord contains stem cells similar to those found in adult bone marrow. And since umbilical cord cells are easy to collect and, in some ways, close in character to embryonic stem cells, cord blood transplants have gradually become an alternative to bone marrow transplants for treating blood disorders.

Other recent studies have probed the potential for cord blood cells to repair damage to the nervous system. When mice with the familial (inherited) form of ALS were given a systemic injection of human umbilical cord blood cells, they lived about 10 percent longer than mice that didn't get the treatment.

Source: MDA/ALS Newsletter, May 2002

Gene Therapy:

MDA grantee Gyula Acsadi of the Departments of Pediatrics and Neurology at Wayne State University in Detroit was on a team that recently slowed disease progression in mice with ALS by using an innovative gene therapy technique. In one set of experiments, Acsadi and colleagues inserted nerve-nourishing genes into adenoviruses and injected the gene-carrying viruses into the back and leg muscles of mice with ALS.

The researchers used a gene, a natural substance that nourishes and helps preserve nerve cells, including motor neurons, the muscle-controlling nerve cells affected in ALS. The treated mice began showing symptoms about a week later than their untreated counterparts and preserved motor function one to two weeks longer. They also lived an average of 17 days longer. The scientists believe the gene probably extended the lives of motor neurons in the spinal cords of the mice, and by slowing the disease progression by a similar degree in humans could add several years to the life of a person with ALS.