Posts tagged ALS
Articles and news from the latest research reports.
Engineered stem cell advance points toward treatment for ALS
Transplantation of human stem cells in an experiment conducted at the University of Wisconsin-Madison improved survival and muscle function in rats used to model ALS, a nerve disease that destroys nerve control of muscles, causing death by respiratory failure.
ALS (amyotrophic lateral sclerosis) is sometimes called “Lou Gehrig’s disease.” According to the ALS Association, the condition strikes about 5,600 Americans each year. Only about half of patients are alive three years after diagnosis.
In work recently completed at the UW School of Veterinary Medicine, Masatoshi Suzuki, an assistant professor of comparative biosciences, and his colleagues used adult stem cells from human bone marrow and genetically engineered the cells to produce compounds called growth factors that can support damaged nerve cells.
The researchers then implanted the cells directly into the muscles of rats that were genetically modified to have symptoms and nerve damage resembling ALS.
In people, the motor neurons that trigger contraction of leg muscles are up to three feet long. These nerve cells are often the first to suffer damage in ALS, but it’s unclear where the deterioration begins. Many scientists have focused on the closer end of the neuron, at the spinal cord, but Suzuki observes that the distant end, where the nerve touches and activates the muscle, is often damaged early in the disease.
The connection between the neuron and the muscle, called the neuro-muscular junction, is where Suzuki focuses his attention. “This is one of our primary differences,” Suzuki says. “We know that the neuro-muscular junction is a site of early deterioration, and we suspected that it might be the villain in causing the nerve cell to die. It might not be an innocent victim of damage that starts elsewhere.”
Previously, Suzuki found that injecting glial cell line-derived neurotropic factor (GDNF) at the junction helped the neurons survive. The new study, published in the journal Molecular Therapy on May 28, expands the research to show a similar effect from a second compound, called vascular endothelial growth factor.
In the study, Suzuki found that using stem cells to deliver vascular endothelial growth factor alone improved survival and delayed the onset of disease and the decline in muscle function. That result mirrored his earlier study with GDNF.
But the real advance, Suzuki says, was finding an even better result from using stem cells that create both of these two growth factors. “In terms of disease-free time, overall survival, and sustaining muscle function, we found that delivering the combination was more powerful than either growth factor alone. The results would provide a new hope for people with this terrible disease.”
The new research was supported by the ALS Association, the National Institutes of Health, the University of Wisconsin Foundation, and other groups.
The injected stem cells survived for at least nine weeks, but did not become neurons. Instead, their contribution was to secrete one or both growth factors.
Originally, much of the enthusiasm for stem cells focused on the hope of replacing damaged cells, but Suzuki’s approach is different. “These motor nerve cells have extremely long connections, and replacing these cells is still challenging. But we aim to keep the neurons alive and healthy using the same growth factors that the body creates, and that’s what we have shown here.”
For the test, Suzuki used ALS model rats with a mutation that is found in a small percentage of ALS patients who have a genetic form of the disease. “This model has been accepted as the best test bed for ALS experiments,” says Suzuki.
By using adult mesenchymal stem cells, the technique avoided the danger of tumor that can arise with the transplant of embryonic stem cells and related “do-anything” cells. Importantly, mesenchymal stem cells have been already used in clinical trials for various human diseases.
In the future, Suzuki hopes to apply his approach by using clinical grade stem cells. “Because this is a fatal and untreatable disease, we hope this could enter a clinical trial relatively soon.”
Researchers identify genetic suspects in sporadic Lou Gehrig’s disease
Researchers at the Stanford University School of Medicine have identified mutations in several new genes that might be associated with the development of spontaneously occurring cases of the neurodegenerative disease known as amyotrophic lateral sclerosis, or ALS. Also known as Lou Gehrig’s disease, the progressive, fatal condition, in which the motor neurons that control movement and breathing gradually cease to function, has no cure.
Although researchers know of some mutations associated with inherited forms of ALS, the majority of patients have no family history of the disease, and there are few clues as to its cause. The Stanford researchers compared the DNA sequences of 47 patients who have the spontaneous form of the disease, known as sporadic ALS, with those of their unaffected parents. The goal was to identify new mutations that were present in the patient but not in either parent that may have contributed to disease development.
Several suspects are mutations in genes that encode chromatin regulators — cellular proteins that govern how DNA is packed into the nucleus of a cell and how it is accessed when genes are expressed. Protein members of one these chromatin-regulatory complexes have recently been shown to play roles in normal development and some forms of cancer.
"The more we know about the genetic causes of the disorder, the greater insight we will have as to possible therapeutic targets," said Aaron Gitler, PhD, associate professor of genetics. "Until now, researchers have primarily relied upon large families with many cases of inherited ALS and attempted to pinpoint genetic regions that seem to occur only in patients. But more than 90 percent of ALS cases are sporadic, and many of the genes involved in these cases are unknown."
Gitler is the senior author of the study, published online May 26 in Nature Neuroscience. Postdoctoral scholar Alessandra Chesi, PhD, is the lead author. Gitler and Chesi collaborated with members of the laboratory of Gerald Crabtree, MD, professor of developmental biology and of pathology. Crabtree, a Howard Hughes Medical Institute investigator, is also a co-author of the study.
Chesi and Gitler combined deductive reasoning with recent advances in sequencing technology to conduct the work, which relied on the availability of genetic samples from not only ALS patients, but also the patients’ unaffected parents. Such trios can be difficult to obtain for diseases like sporadic ALS that strike well into adulthood when a patient’s parents may no longer be alive. Gitler and Chesi collaborated with researchers from Emory University and Johns Hopkins University to collect these samples.
The researchers compared the sequences of a portion of the genome called the exome, which directly contributes to the amino acid sequences of all the proteins in a cell. (Many genes contain intervening, non-protein-coding regions of DNA called introns that are removed prior to protein production.) Mutations found only in the patient’s exome, but not in that of his or her parents’, were viewed as potential disease-associated candidates - particularly if they affected the composition or structure of the resulting protein made from that gene.
Focusing on just the exome, which is about 1 percent of the total amount of DNA in each human cell, vastly reduced the total amount of DNA that needed to be sequenced and allowed the researchers to achieve relatively high coverage (or repeated sequencing to ensure accuracy) of each sample.
"We wanted to find novel changes in the patients," Chesi said. "These represent a class of mutations called de novo mutations that likely occurred during the production of the parents’ reproductive cells." As a result, these mutations would be carried in all the cells of patients, but not in their parents or siblings.
Using the exome sequencing technique, the researchers identified 25 de novo mutations in the ALS patients. Of these, five are known to be in genes involved in the regulation of the tightly packed form of DNA called chromatin — a proportion that is much higher than would have been expected by chance, according to Chesi.
Furthermore, one of the five chromatin regulatory proteins, SS18L1, is a member of a neuron-specific complex called nBAF, which has long been studied in Crabtree’s laboratory. This complex is strongly expressed in the brain and spinal cord, and affects the ability of the neurons to form branching structures called dendrites that are essential to nerve signaling.
"We found that, in one sporadic ALS case, the last nine amino acids of this protein are missing," Gitler said. "I knew that Gerald Crabtree’s lab had been investigating SS18L1, so I asked him about it. In fact, they had already identified these amino acids as being very important to the function of the protein."
When the researchers expressed the mutant SS18L1 in motor neurons isolated from mouse embryos, they found the neurons were unable to extend and grow new dendrites as robustly as normal neurons in response to stimuli. They also showed that SS18L1 appears to physically interact with another protein known to be involved in cases of familial, or inherited, ALS.
Although the results are intriguing, the researchers caution that more work is necessary to conclusively prove whether and how mutations in SS18L1 contribute to sporadic cases of ALS. But now they have an idea of where to look in other patients, without requiring the existence of patient and parent trios. They are planning to sequence SS18L1 and other candidates in an additional few thousand sporadic ALS cases.
"This is the first systematic analysis of ALS triads for the presence of de novo mutations," Chesi said. "Now we have a list of candidate genes we can pursue. We haven’t proven that these mutations cause ALS, but we’ve shown, at least in the context of SS18L1, that the mutation carried by some patients is damaging to the protein and affects the ability of mouse motor neurons to form dendrites."
(Source: med.stanford.edu)
Painting through the power of thought enabled by scientists
To the viewer it is an accomplished semiabstract image of flowers and clouds, but in fact this painting was produced by a paralysed woman solely through the power of thought.
Heide Pfützner, a former teacher from Leipzig, Germany, was diagnosed with Amyotrophic Lateral Sclerosis, also known as Motor Neurone Disease, yet she has managed to produce a series of the paintings with the aid of a new brain controlled computer.
She has been trained to master the device that uses brain waves to take control of a palette of colours, shapes and brushes to produce digital artworks.
Building on decades of knowledge about the meaning of the tiny electrical impulses created by the brain during thought, scientists have been able to create a computer programme which translates thoughts into electronic images.
As well as helping patients with progressive brain diseases like Mrs Pfützner, other users of the device include those who are “locked in” to a physically unresponsive state and therefore unable to communicate with the rest of the world.
The system works by detecting changes in the pattern of the user’s brain waves to allow them to select options in software and to move a cursor around a screen in front of them.
Read moreNeon exposes hidden ALS cells
A small group of elusive neurons in the brain’s cortex play a big role in ALS (amyotrophic lateral sclerosis), a swift and fatal neurodegenerative disease that paralyzes its victims. But the neurons have always been difficult to study because there are so few of them and they look so similar to other neurons in the cortex.
In a new preclinical study, a Northwestern Medicine® scientist has isolated the motor neurons in the brain that die in ALS and, for the first time, dressed them in a green fluorescent jacket. Now they’re impossible to miss and easy to study.
The cells slide on neon jackets when they are born and continue to wear them as they age and become sick. As a result, scientists will now be able to track what goes wrong in these cells to cause their deaths and be able to search for effective treatments.
"We have developed the tool to investigate what makes these cells become vulnerable and sick," said Hande Ozdinler, senior author of the study and assistant professor of neurology at Northwestern University Feinberg School of Medicine. "This was not possible before."
Ozdinler and colleagues also identified the motor neurons that don’t die, enabling scientists to study what protects them.
The study will be published in the Journal of Neuroscience on May 1.
ALS, also known as Lou Gehrig’s disease, causes the death of muscle-controlling nerve cells in the brain and spinal cord (motor neurons). It results in rapidly progressing paralysis and death usually within three to five years of the onset of symptoms.
There are about 75,000 upper motor neurons affected in ALS out of some 2 billion cells in the brain. Previously, the only way to study the upper motor neurons was to extract them through surgery, a difficult process that was beyond the scope of most scientists and still didn’t allow examination of the ailing neurons at various stages of the disease.
"You couldn’t study them at the cellular level, so the research field ignored them," Ozdinler said. She is one of the few scientists in the country who studies cortical motor neurons. Most of ALS research has focused on the death of motor neurons in the spinal cord.
Key puzzle piece: Why ALS moves so swiftly
But the brain’s motor neurons are a key piece of the ALS puzzle. Their disintegration explains why the disease advances more swiftly than other neurodegenerative diseases. It had previously been thought that the spinal motor neurons died first and their demise led to the secondary death of the brain’s motor neurons. But Ozdinler’s recent research showed that the motor neurons in the brain and spinal cord die simultaneously.
"The whole system collapses at once," Ozdinler said. "It’s degeneration from both ends which is why the disease moves so swiftly."
Every voluntary movement is initiated and modulated by upper motor neurons — answering a cell phone, typing an email, walking to the store. The upper motor neurons tell the spinal motor neurons what to do. In ALS, both the directing neurons and the neurons that create the movement disintegrate at the same time.
Finding the light that never goes out
Ozdinler spent the last four years figuring out how to permanently sheath cortical motor neurons in fluorescence.
Although scientists can flag spinal cord motor neurons in fluorescence, it wears off as the neuron ages because the process uses an embryonic gene. Ozdinler wanted a longer lasting effect so scientists could study the neuron as it ages and develops ALS. She sorted through 6,000 upper motor neuron genes that are vulnerable to ALS before she found one — UCHL1 — that is expressed through adulthood.
She used that gene — which had been cloned with the fluorescence molecule — and created a mouse model whose upper motor neurons shimmer in green. Then she mated that mouse with an ALS transgenic mouse model. The result is a mouse with fluorescent diseased motor neurons in the brain.
"Now we have a model of one motor neuron population that dies and one that is resistant," Ozdinler said. "That’s the perfect experiment. You can ask what does this neuron have that makes it resistant and what does the other one have that makes it vulnerable? That’s what we will find out."
Marina Yasvoina, a graduate student, and Baris Genc, a postdoctoral fellow, both in Ozdinler’s lab, are the lead authors of the paper. Ozdinler collaborated with Gordon Shepherd, associate professor of physiology, and C.J. Heckman, professor in physiology, both at Feinberg.
"This work was possible thanks to the collaborative nature of Northwestern," Ozdinler said.
(Source: eurekalert.org)
Melatonin delays ALS symptom onset and death in mice
Melatonin injections delayed symptom onset and reduced mortality in a mouse model of the neurodegenerative condition amyotrophic lateral sclerosis (ALS), or Lou Gehrig’s disease, according to a new study by researchers at the University of Pittsburgh School of Medicine. In a report published online ahead of print in the journal Neurobiology of Disease, the team revealed that receptors for melatonin are found in the nerve cells, a finding that could launch novel therapeutic approaches.
Annually about 5,000 people are diagnosed with ALS, which is characterized by progressive muscle weakness and eventual death due to the failure of respiratory muscles, said senior investigator Robert Friedlander, M.D., UPMC Endowed Professor of neurosurgery and neurobiology and chair, Department of Neurological Surgery, Pitt School of Medicine. But the causes of the condition are not well understood, thwarting development of a cure or even effective treatments.
Melatonin is a naturally occurring hormone that is best known for its role in sleep regulation. After screening more than a thousand FDA-approved drugs several years ago, the research team determined that melatonin is a powerful antioxidant that blocks the release of enzymes that activate apoptosis, or programmed cell death.
"Our experiments show for the first time that a lack of melatonin and melatonin receptor 1, or MT1, is associated with the progression of ALS," Dr. Friedlander said. "We saw similar results in a Huntington’s disease model in an earlier project, suggesting similar biochemical pathways are disrupted in these challenging neurologic diseases."
Hoping to stop neuron death in ALS just as they did in Huntington’s, the research team treated mice bred to have an ALS-like disease with injections of melatonin or with a placebo. Compared to untreated animals, the melatonin group developed symptoms later, survived longer, and had less degeneration of motor neurons in the spinal cord.
"Much more work has to be done to unravel these mechanisms before human trials of melatonin or a drug akin to it can be conducted to determine its usefulness as an ALS treatment," Dr. Friedlander said. "I suspect that a combination of agents that act on these pathways will be needed to make headway with this devastating disease."
(Source: eurekalert.org)
ALS trial shows novel therapy is safe
An investigational treatment for an inherited form of Lou Gehrig’s disease has passed an early phase clinical trial for safety, researchers at Washington University School of Medicine in St. Louis and Massachusetts General Hospital report.
The researchers have shown that the therapy produced no serious side effects in patients with the disease, also known as amyotrophic lateral sclerosis (ALS). The phase 1 trial’s results, available online in Lancet Neurology, also demonstrate that the drug was successfully introduced into the central nervous system.
The treatment uses a technique that shuts off the mutated gene that causes the disease. This approach had never been tested against a condition that damages nerve cells in the brain and spinal cord.
“These results let us move forward in the development of this treatment and also suggest that it’s time to think about applying this same approach to other mutated genes that cause central nervous system disorders,” says lead author Timothy Miller, MD, PhD, assistant professor of neurology at Washington University. “These could include some forms of Alzheimer’s disease, Parkinson’s disease, Huntington’s disease and other conditions.”
ALS destroys nerves that control muscles, gradually leading to paralysis and death. For treatment of the disease, the sole FDA-approved medication, Riluzole, has only a marginal effect.
Most cases of ALS are sporadic, but about 10 percent are linked to inherited mutations. Scientists have identified changes in 10 genes that can cause ALS and are still looking for others.
The study focused on a form of ALS caused by mutations in a gene called SOD1, which account for 2 percent of all ALS cases. Researchers have found more than 100 mutations in the SOD1 gene that cause ALS.
“At the molecular level, these mutations affect the properties of the SOD1 protein in a variety of ways, but they all lead to ALS,” says Miller, who is director of the Christopher Wells Hobler Lab for ALS Research at the Hope Center for Neurological Disorders at Washington University.
Rather than try to understand how each mutation causes ALS, Miller and his colleagues focused on blocking production of the SOD1 protein using a technique called antisense therapy.
To make a protein, cells have to copy the protein-building instructions from the gene. Antisense therapy blocks the cell from using these copies, allowing researchers to selectively silence individual genes.
“Antisense therapy has been considered and tested for a variety of disorders over the past several decades,” Miller says. “For example, the FDA recently approved an antisense therapy called Kynamro for familial hypercholesterolemia, an inherited condition that increases cholesterol levels in the blood.”
Miller and colleagues at the University of California-San Diego devised an antisense drug for SOD1 and successfully tested it in an animal model of the disease.
Merit Cudkowicz, MD, chief of neurology at Massachusetts General Hospital, was co-PI of the phase I clinical safety trial described in the new paper. Clinicians at Barnes-Jewish Hospital, Massachusetts General Hospital, Johns Hopkins Hospital and the Methodist Neurological Institute in Houston gave antisense therapy or a placebo to 21 patients with SOD1-related ALS. Treatment consisted of spinal infusions that lasted 11 hours.
The scientists found no significant difference between side effects in the control and treatment groups. Headache and back pain, both of which are often associated with spinal infusion, were among the most common side effects.
Immediately after the injections, the researchers took spinal fluid samples. This let them confirm the antisense drug was circulating in the spinal fluid of patients who received the treatment.
To treat SOD1-related ALS in the upcoming phase II trial, researchers will need to increase the dosage of the antisense drug. As the dose rises, they will watch to ensure that the therapy does not cause harmful inflammation or other side effects as it lowers SOD1 protein levels.
“All the information that we have so far suggests lowering SOD1 will be safe,” Miller says. “In fact, completely disabling SOD1 in mice seems to have little to no effect. We think it will be OK in patients, but we won’t know for sure until we’ve conducted further trials.”
The therapy may one day be helpful in the more common, noninherited forms of ALS, some of which may be linked to problems with the SOD1 protein.
“Before we can consider using this same therapy for sporadic ALS, we need more evidence that SOD1 is a major contributor to these forms of the disorder,” Miller says.
The trial was conducted with support from ISIS Pharmaceuticals, which co-owns a patent on the SOD1 antisense drug.
Big boost in drug discovery: New use for stem cells identifies a promising way to target ALS
Using a new, stem cell-based, drug-screening technology that could reinvent and greatly reduce the cost of developing pharmaceuticals, researchers at the Harvard Stem Cell Institute (HSCI) have found a compound that is more effective in protecting the neurons killed in amyotrophic lateral sclerosis (ALS) than are two drugs that failed in human clinical trials after large sums were invested in them.
The new screening technique developed by Lee Rubin, a member of HSCI’s executive committee and a professor in Harvard’s Department of Stem Cell and Regenerative Biology (SCRB), had predicted that the two drugs that eventually failed in the third and final stage of human testing would do just that.
“It’s a deep, dark secret of drug discovery that very few drugs have been tested on human-diseased cells before being tested in a live person,” said Rubin, who heads HSCI’s program in translational medicine. “We were interested in the notion that we can use stem cells to correct that situation.”
Rubin’s model is built on an earlier proof of concept developed by HSCI principal faculty member Kevin Eggan, who demonstrated that it was possible to move a neuron-based disease into a laboratory dish using stem cells carrying the genes of patients with the disease.
In a paper published today in the journal Cell Stem Cell, Rubin laid out how he and his colleagues applied their new method of stem cell-based drug discovery to ALS, also known as Lou Gehrig’s disease. The illness is associated with the progressive death of motor neurons, which pass information between the brain and the muscles. As cells die, people with ALS experience weakness in their limbs, followed by rapid paralysis and respiratory failure. The disease typically strikes later in life. Ten percent of cases are genetically predisposed, but for most patients there is no known trigger.
Rubin’s lab began by studying the disease in mice, growing billions of motor neurons from mouse embryonic stem cells, half normal and half with a genetic mutation known to cause ALS. Investigators starved the cells of nutrients and then screened 5,000 druglike molecules to find any that would keep the motor neurons alive.
Several hits were identified, but the molecule that best prolonged the life of both normal and ALS motor neurons was kenpaullone, previously known for blocking the action of an enzyme (GSK-3) that switches on and off several cellular processes, including cell growth and death. “Shockingly, this molecule keeps cells alive better than the standard culture medium that everybody keeps motor neurons in,” Rubin said.
Kenpaullone proved effective in several follow-up experiments that put mouse motor neurons in situations of certain death. Neuron survival increased in the presence of the molecule whether the cells were programmed to die or were placed in a toxic environment.
After further investigation, Rubin’s lab discovered that kenpaullone’s potency came from its ability also to inhibit HGK, an enzyme that sets off a chain of reactions that leads to motor neuron death. This enzyme was not previously known to be important in motor neurons or associated with ALS, marking the discovery of a new drug target for the disease.
“I think that stem cell screens will discover new compounds that have never been discovered before by other methods,” Rubin said. “I’m excited to think that someday one of them might actually be good enough to go into the clinic.”
To find out if kenpaullone worked in diseased human cells, Rubin’s lab exposed patient motor neurons and motor neurons grown from human embryonic stem cells to the molecule, as well as two drugs that did well in mice but failed in phase III human clinical trials for ALS. Once again, kenpaullone increased the rate of neuron survival, while one drug saw little response, and the other drug failed to keep any cells alive.
According to Rubin, before kenpaullone could be used as a drug, it would need a substantial molecular makeover to make it better able to target cells and find its way into the spinal cord so it can access motor neurons.
“This is kind of a proof of principle on the do-ability of the whole thing,” he said. “I think it’s possible to use this method to discover new drug targets and to prevalidate compounds on real human disease cells before putting them in the clinic.”
Rubin’s next steps will be to continue searching for better druglike compounds that can inhibit HGK and thus enhance motor neuron survival. He believes that the new information that comes out of this research will be useful to academia and the pharmaceutical industry.
“These kinds of exploratory screens are hard to fund, so being part of the HSCI” — which provided some of the funding — “has been absolutely essential,” Rubin said.
(Source: news.harvard.edu)
Researchers discover new treatment possibilities for Lou Gehrig’s disease
A team led by Dr. Alex Parker, a professor of pathology and cellular biology and a researcher at the University of Montreal Hospital Research Centre (CRCHUM), has identified an important therapeutic target for alleviating the symptoms of Lou Gehrig’s disease, also known as amyotrophic lateral sclerosis (ALS), and other related neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease and Huntington’s disease.
In a study published in the online version of Neurobiology of Disease, the team both confirmed the importance of this new target as well as a series of compounds that can be used to attenuate the dysregulation of one of the important cellular processes that lead to neuronal dysfunction and ultimately to brain cell death.
Although scientists are unclear about causes of ALS, they have made headway in identifying the cellular process potentially implicated in disease onset and progression. One such process which has attracted researcher interest involves the endoplasmic reticulum (ER), a component of cells that plays an important role in maintaining cell health. In collaboration with Dr. Pierre Drapeau at the University of Montreal and using worm and zebrafish models of ALS, Parker’s team not only confirmed that incapacitated ER leads to the motor neuron death typical of ALS, but also identified a series of compounds that alleviate the fatal consequences of defective ER.
“Since Riluzole, the one approved treatment compound for treating ALS, only has a modest effect on slowing disease progression, we set out to test a number of other compounds, and in so doing we discovered that they work by compensating for defective ER” explains Dr Parker. The compounds in question, Methylene blue, Salubrinal, Guanabenz and Phenazine, were each tested individually and in different combinations.
With the exception of Phenazine, these compounds have known benefits for treating neurodegenerative diseases. Parker and his team showed that each of these compounds reduces paralysis and neurodegeneration and that each acts on different parts of the ER pathway to achieve neuroprotection. More importantly, the researchers found that using these compounds in different combinations can enhance their therapeutic effects.
“These results are quite encouraging,” says Dr Parker, “and have given us a much better understanding of ER’s role in ALS as well as showing the way for improved treatments”. Parker’s team plans to test and confirm these findings with more complex animal models, a necessary step in developing medication that can be of benefit to human beings.
(Source: nouvelles.umontreal.ca)
Phase 1 ALS trial is first to test antisense treatment of neurodegenerative disease
The initial clinical trial of a novel approach to treating amyotrophic lateral sclerosis (ALS) – blocking production of a mutant protein that causes an inherited form of the progressive neurodegenerative disease – may be a first step towards a new era in the treatment of such disorders. Investigators from Massachusetts General Hospital (MGH) and Washington University School of Medicine report that infusion of an antisense oligonucleotide against SOD1, the first gene to be associated with familial ALS, had no serious adverse effects and the drug was successfully distributed thoughout the central nervous system.
"This therapy directly targets the cause of this form of ALS – a mutation in SOD1, which was originally discovered here at the MGH by my mentor Robert Brown," says Merit Cudkowicz, MD, chief of Neurology at MGH and senior author of the report in Lancet Neurology, which has been released online. “It’s very exciting that we have reached a stage when we can start clinical trials against this type of ALS.”
ALS causes the death of motor neurons in the brain and spinal cord, stopping transmission of neural signals to nerve fibers and leading to weakness, paralysis and usually death from respiratory failure. Only 10 percent of ALS cases are inherited, and mutations in SOD1 – which produce an aberrant, toxic form of the protein – account for about 20 percent of familial cases. Although that first SOD1 mutation was identified 20 years ago by the team lead by Brown – who is now professor and chief of Neurology at the University of Massachusetts Medical School – a technology that directly addresses such mutations became available only recently.
The current study, the first author of which is Timothy Miller, MD, PhD, of Washington University, used what are called antisense oligonucleotides – small, single-stranded DNA or RNA molecules that prevent production of a protein by binding to its messenger RNA. While antisense medications have been tested against several types of disease, this was the first trial in a neurological disorder, making the assurance of safety – a primary goal of a phase 1 study – particular important. Studies in animal models led by Miller and others found that the experimental antisense drug used in this trial reduced expression of mutated and nonmutated SOD1 and slowed the progression of ALS.
Conducted at the MGH, Washington University, Johns Hopkins University and the Methodist Neurological Institute in Houston, the trial enrolled a total of 21 patients with SOD1 familial ALS. Four sequential groups of participants received spinal infusions over an 11-hour period of the antisense drug or a placebo, with the active drug being administered at one of four dosage levels. Since participants in one group were free to join a subsequent group more than 60 days later, seven received two infusions and two received a total of three.
Some of the participants reported the type of adverse effects typically associated with spinal infusions – headache and back pain – with no difference between the active drug and placebo groups. Participants who receive subsequent infusions reported fewer adverse effects. Cerebrospinal fluid samples taken immediately after infusion revealed the presence of the antisense oligonucleotidein all participants receiving the drug at levels close to what was predicted based on animal studies. Analysis of spinal cord samples from one participant who had later died from ALS found drug levels highest at the site of the infusion and lowest at the furthest point and suggested that prior estimates of how long the drug would persist in the spinal cord were accurate.
Cudkowicz notes that the next step will be a larger study to address long-term safety and take a first look at the effectiveness of antisense treatment against ALS “This is a very important step forward for neurodegenerative disorders in general,” she explains. “There are other ALS gene mutations that antisense technology may be useful against. There also is an ongoing study of a different oligonucleotide against spinal muscular atrophy, and ongoing preclinical studies in Huntington’s disease, myotonic dystrophy and other neurological disorders are in development.
"The first person with ALS that I cared for had SOD1 ALS," she adds, "and I promised her a commitment to finding a treatment for this form of the disease. It’s so gratifying to finally be at the stage of knowledge where we can start testing this treatment in patients with SOD1 ALS. We also hope that this treatment may apply to the broader population of patient with sporadic ALS." Cudkowicz is the Julieanne Dorn Professor of Neurology at Harvard Medical School.
(Source: massgeneral.org)
Researchers Discover New Clues About How Amyotrophic Lateral Sclerosis (ALS) Develops
Johns Hopkins scientists say they have evidence from animal studies that a type of central nervous system cell other than motor neurons plays a fundamental role in the development of amyotrophic lateral sclerosis (ALS), a fatal degenerative disease. The discovery holds promise, they say, for identifying new targets for interrupting the disease’s progress.
In a study described online in Nature Neuroscience, the researchers found that, in mice bred with a gene mutation that causes human ALS, dramatic changes occurred in oligodendrocytes — cells that create insulation for the nerves of the central nervous system — long before the first physical symptoms of the disease appeared. Oligodendrocytes located near motor neurons — cells that govern movement — died off at very high rates, and new ones regenerated in their place were inferior and unhealthy.
The researchers also found, to their surprise, that suppressing an ALS-causing gene in oligodendrocytes of mice bred with the disease — while still allowing the gene to remain in the motor neurons — profoundly delayed the onset of ALS. It also prolonged survival of these mice by more than three months, a long time in the life span of a mouse. These observations suggest that oligodendrocytes play a very significant role in the early stage of the disease.
“The abnormalities in oligodendrocytes appear to be having a negative impact on the survival of motor neurons,” says Dwight E. Bergles, Ph.D., a co-author and a professor of neuroscience at the Johns Hopkins University School of Medicine. “The motor neurons seem to be dependent on healthy oligodendrocytes for survival, something we didn’t appreciate before.”
“These findings teach us that cells we never thought had a role in ALS not only are involved but also clearly contribute to the onset of the disease,” says co-author Jeffrey D. Rothstein, M.D., Ph.D., a professor of neurology at Johns Hopkins and director of the Johns Hopkins Medicine Brain Science Institute.
Scientists have long believed that oligodendrocytes functioned only as structural elements of the central nervous system. They wrap around nerves, making up the myelin sheath that provides the “insulation” that allows nerve signals to be transmitted rapidly and efficiently. However, Rothstein and others recently discovered that oligodendrocytes also deliver essential nutrients to neurons, and that most neurons need this support to survive.
The Johns Hopkins team of Bergles and Rothstein published a paper in 2010 that described in mice with ALS an unexpected massive proliferation of oligodendrocyte progenitor cells in the spinal cord’s motor neurons, and that these progenitors were being mobilized to make new oligodendrocytes. The researchers believed that these cells were multiplying because of an injury to oligodendrocytes, but they weren’t sure what was happening. Using a genetic method of tracking the fate of oligodendrocytes, in the new study, the researchers found that cells present in young mice with ALS were dying off at an increasing rate in concert with advancing disease. Moreover, the development of the newly formed oligodendrocytes was stalled and they were not able to provide motor neurons with a needed source of cell nutrients.
To determine whether the changes to the oligodendrocytes were just a side effect of the death of motor neurons, the scientists used a poison to kill motor neurons in the ALS mice and found no response from the progenitors, suggesting, says Rothstein, that it is the mutant ALS gene that is damaging oligodendrocytes directly.
Meanwhile, in separate experiments, the researchers found similar changes in samples of tissues from the brains of 35 people who died of ALS. Rothstein says it may be possible to see those changes early on in the disease and use MRI technology to follow progression.
“If our research is confirmed, perhaps we can start looking at ALS patients in a different way, looking for damage to oligodendrocytes as a marker for disease progression,” Rothstein says. “This could not only lead to new treatment targets but also help us to monitor whether the treatments we offer are actually working.”
ALS, also known as Lou Gehrig’s disease, named for the Yankee baseball great who died from it, affects nerve cells in the brain and spinal cord that control voluntary muscle movement. The nerve cells waste away or die, and can no longer send messages to muscles, eventually leading to muscle weakening, twitching and an inability to move the arms, legs and body. Onset is typically around age 50 and death often occurs within three to five years of diagnosis. Some 10 percent of cases are hereditary.
There is no cure for ALS and there is only one FDA-approved drug treatment, which has just a small effect in slowing disease progression and increasing survival.
Even though myelin loss has not previously been thought to occur in the gray matter, a region in the brain where neurons process information, the researchers in the new study found in ALS patients a significant loss of myelin in one of every three samples of human tissue taken from the brain’s gray matter, suggesting that the oligodendrocytes were abnormal. It isn’t clear if the oligodendrocytes that form this myelin in the gray matter play a different role than in white matter — the region in the brain where signals are relayed.
The findings further suggest that clues to the treatment of other diseases long believed to be focused in the brain’s gray matter — such as Alzheimer’s disease, Huntington’s disease and Parkinson’s disease — may be informed by studies of diseases of the white matter, such as multiple sclerosis (MS). Bergles says ALS and MS researchers never really thought their diseases had much in common before.
Oligodendrocytes have been under intense scrutiny in MS, Bergles says. In MS, the disease over time can transform from a remitting-relapsing form — in which myelin is attacked but then is regenerated when existing progenitors create new oligodendrocytes to re-form myelin — to a more chronic stage in which oligodendrocytes are no longer regenerated. MS researchers are working to identify new ways to induce the creation of new oligodendrocytes and improve their survival. “It’s possible that we may be able to dovetail with some of the same therapeutics to slow the progression of ALS,” Bergles says.
(Source: newswise.com)