amyotrophic lateral sclerosis

Spasticity in MND Improved With Cannabinoid Oral Spray

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Nabiximols, a cannabinoid-based oral spray (Sativex, GW Pharmaceuticals) approved outside the United States for various multiple sclerosis (MS) symptoms, shows benefit in improving spasticity and pain in motor neuron disease when administered as an add-on to standard therapy, new research suggests.

“This study is, to our knowledge, the first randomized controlled trial of safety and efficacy of a pharmacological treatment for spasticity and the first trial of nabiximols in motor neuron disease,” write the authors in their article published online December 13 in Lancet Neurology.

“Our results suggest that the study drug is well tolerated and provides first evidence of efficacy in terms of controlling spasticity in patients with motor neuron disease.”

Current treatments commonly used for spasticity in motor neuron diseases such as amyotrophic lateral sclerosis (ALS), the most common and severe of these diseases, including baclofen, dantrolene, and benzodiazepines, lack evidence of efficacy in this context and are associated with undesirable side effects including increased muscle weakness or fatigue.

Nabiximols, an oral spray combining equal parts delta-9 tetrahydrocannabinol and cannabidiol (THC-CBD), has meanwhile gained favor in the treatment of spasticity in MS in countries outside of the United States where it is licensed, suggesting potential for efficacy in spasticity in other diseases.

For the current proof-of-concept study, first author Nilo Riva, MD, of the IRCCS San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy, and colleagues enrolled 60 patients with at least 3 months of spasticity symptoms associated with known or suspected ALS or primary lateral sclerosis (PLS) who were already taking an anti-spasticity regimen for at least 30 days prior to enrollment.

Patients were randomized to add-on treatment with nabiximols at an escalated dose to a predefined level titrated over 14 days or placebo for 6 weeks.

The study reached its primary endpoint with improvement in spasticity, assessed by change in the spasticity score of the Modified Ashworth Scale (MAS), which measures intensity of muscle tone, by a mean of 0.11 (SD, 0.48) in the nabiximols group (n = 59) compared with a deterioration of a mean of 0.16 (SD, 0.47) in the placebo group (n = 30; P = .01) over the course of the study.

Greater improvements were also observed in pain scores, reported on a scale of 0 to 10, with nabiximols (-0.97 vs -0.06) and in patient-reported global impression of change (P = .001).

Although there were no significant differences in other secondary endpoints, including sleep quality, spasms, spasticity, strength, upper and lower motor neuron tests, and scores on the Amyotrophic Lateral Sclerosis Functional Rating Scale — Revised, the scores suggested some benefit, Riva told Medscape Medical News.

“Although the effects on spasms, sleep disruption, and spasticity NRS scores were not significant, the direction of change was consistently in favor of the active treatment, and the pain NRS score improved significantly in nabiximols recipients,” Riva said.

The improvement was especially notable considering the patients’ existing regimens were falling short, Riva explained.

“The first-line anti-spasticity medications, including general muscle relaxants such as baclofen or benzodiazepines, usually work for some time, but as disease evolves, which can happen in months in ALS, the muscle rigidity may increase and a good number of patients require new management options,” said Riva.

Improvement in pain, which is also reported with the use of cannabinoids in other conditions, is also notably important, considering that it is a common complaint among people with motor neuron disease, Riva added.

“Although pain is an often neglected symptom in motor neuron disease, its prevalence has been reported to be as high as 51% to 80%, it negatively affects quality of life, and it necessitates specific treatment in 37% to 39% of patients.”

Similar to a previous study of cramps in ALS, no significant changes specifically in the intensity of spasms were seen in the study.

There were no serious adverse events. Although 21 (72%) of participants in the nabiximols group had at least one potentially treatment-related adverse event, compared with four in the placebo group (13%), none of the patients permanently discontinued treatment during the double-blind phase.

Non-serious adverse events were described as modest and were consistent with those common to cannabinoid treatment: three patients in the nabiximols group temporarily discontinuing treatment, one because of nausea and anxiety, one who had influenza and experienced a fall, and one who had disease progression.

Although nabiximols contain THC, the psychoactive component of cannabis, Riva noted that the levels are much lower than those typically associated with cannabis.

“The maximal levels of THC in blood (Cmax) reached with this oromucosal spray medication are about 60 times lower than the levels reached through THC inhalation, so no psychoses-like effects were expected,” Riva said.

“The medication has been used in Europe by tens of thousands of multiple sclerosis patients [for] years without major psychoactive cases.”

Meanwhile, the THC is believed to have an important role in the anti-spasticity effect of nabiximols, Riva added. “The muscle relaxant effect of the medication has been related to low and continuous levels of THC, as well as analgesia.

“Cannabidiol alone has shown effect on epilepsy area, but not in a relevant manner on muscle relaxation or pain to my knowledge.”

After the 6-week double-blind phase of the study, all participants had the opportunity to enroll in an open-label phase, and among them, two patients did not continue and seven patients ended up withdrawing from the open-label phase because of side effects or disease progression.

Meanwhile, participants who had been in the placebo group showed substantial improvements in mean MAS scores during the open-label phase.

“The (extension findings) further support nabiximols’ efficacy, even if the open-label design excludes the possibility of drawing any definitive conclusion,” Riva said.

Limitations of the study include that the MAS, despite being the most used and best validated objective measure of spasticity, may not fully represent patients’ experience of spasticity, and self-reported measures may also fall short in accurately representing spasticity, the authors noted.

“The ideal objective measure of the highly complex symptom of spasticity does not exist,” they said.

In an accompanying commentary, Marianne de Visser, MD, PhD, professor of neuromuscular disorders at Amsterdam University Medical Centre, the Netherlands, noted that limitations of the study include a bias towards patients who primarily had involvement of upper motor neurons in the nabiximols group.

“These patients (with upper motor neuron involvement) could have benefited more than the 13 patients with classic ALS, which involves both upper and lower motor neurons,” de Visser said.

Further commenting to Medscape Medical News, de Visser added that focusing on spasticity as a prevailing symptom, in general, could be a limitation.

“As yet, there is still uncertainty of how much spasticity contributes to the disease burden in the so-called classical type of ALS — not only spasticity but also flaccid weakness,” she explained.

Although the cannabinoids have shown efficacy and safety in MS, de Visser noted that responses could be different in patients with motor neuron disease.

“The literature on the use of nabiximols in MS seems to be reassuring regarding side effects,” she said. “However, ALS/motor neuron disease is a totally different disease, so we need the larger trials as well in order to assess the adverse effects.”

“The evidence provided (in the current research), albeit in a proof-of-principle study, is encouraging, ” she added.

“Further studies with larger numbers of ALS patients are needed to assess whether nabiximols is not only leading to reduction of spasticity but also reduces disease burden and improves quality of life.”

GW Pharmaceuticals has already made waves in the cannabis-based drug market in the United States this year with its oral drug Epidiolex (cannabidiol), the first drug containing a purified drug component derived from cannabis to receive approval from the US Food and Drug Administration.

What Did Stephen Hawking Do? The Physicist’s 5 Biggest Achievements

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On Wednesday, world-renowned astrophysicist Stephen Hawking died at age 76 in his home in Cambridge, England. He lived for 55 years with the neurological disease amyotrophic lateral sclerosis (ALS), and as a result, he spent most of his life using a wheelchair, which, for the last decade, also included hands-free communication capability that gave him the computerized voice with which so many people now associate him.

As a working physicist and prolific public figure, Hawking helped revolutionize the field of astrophysics. His scholarship helped elucidate our modern understanding of the universe and its origins, and he was quick to share his views on humanity and society. While his achievements are many, there are five in particular worth noting.

Space

5. Stephen Hawking Theorized How Black Holes Emit Information

Black holes are notoriously hungry phenomena, distorting spacetime and sucking in any matter that passes within their event horizon. But Hawking theorized that black holes actually radiate energy as a result of quantum effects near the event horizon. We could only observe this theoretical energy, which is referred to as “Hawking radiation,” in smaller black holes that are about the same mass as our sun. In larger black holes, it would be overwhelmed by the gas falling into the black hole. Hawkin’s hypothesized phenomenon hasn’t been directly observed, but as Inverse previously reported, physicists are working on it.

'Big Bang Theory' loved its nerdy celeb cameos, and Stephen Hawking's was an absolute treasure.

4. Stephen Hawking Proposed That the Singularity Was an Essential Element of the Big Bang Theory

The Big Bang Theory — the physics one, not the television one — proposes the universe began with a powerful expansion that started with one point, the singularity. Before Hawking’s time, physicists tried to reconcile the apparent paradox of the singularity. The idea of a single point of infinite density simply didn’t mesh with the conventional views of physics in the middle of the 20th century. In 1970, though, Hawking co-authored a paper with Roger Penrose that began to reconcile this notion.

This paper, titled “The singularities of gravitational collapse and cosmology,” countered the widely discussed notion that the Big Bang was preceded by the universe contracting. Physicists generally accept this version of the Big Bang Theory, in which there was nothing before the beginning of the universe.

Ripples in spacetime.

3. Stephen Hawking Proposed There Was No Meaningful Distinction Between Space and Time in the Early Universe

In his 1988 best-selling book, A Brief History of Time, Hawking proposed that at the very beginning of the universe, space existed, but time as we know it did not yet exist. Astrophysicists continue to describe space and time as being intrinsically tied to one another, but Hawking hypothesized that at the very beginning of everything there was no meaningful distinction. The curious public digested this hypothesis in Hawking’s book, but physicists continue to debate his idea.

Stephen Hawking, Big Bang

2. Stephen Hawking Provided Evidence That Time Travel Is Impossible

Back in 2009, Hawking hosted a time traveler party, inviting time travelers to join him for a reception to celebrate their achievements. Here’s the catch, though: He didn’t send out the invitations until the next day. The idea was that anyone who actually showed up would clearly be legit since nobody knew about the party before it happened. On Hawking’s 75th birthday in 2017, he announced that nobody had shown up to his party. While this isn’t definitive proof that time travel doesn’t exist, it’s pretty strong evidence. After all, if you discovered how to travel through time, wouldn’t Hawking’s time travel party be one of your first destinations?

Stephen Hawking on 'The Simpsons'

1. Stephen Hawking Played Himself Four Times on The Simpsons

Sure, revolutionizing astrophysics is great, but what about having your cartoon avatar immortalized for posterity? In addition to playing himself on Star Trek, Hawking appeared on The Simpsons four times between 1999 and 2010. Sure, this achievement wasn’t scientific, strictly speaking, but it does embody the character and public image of one of the best-known scientists in modern history. As a physicist, Hawking didn’t create much original work in his later years. But as a science popularizer, he continued to inspire people to learn about the world around them. And as far as monumental achievements go, that one’s hard to overstate.

Stephen Hawking, Given Two Years to Live in 1963, Is Going To Space Over 50 Years Later.

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Dr. Stephen Hawking delivers a speech entitled ‘Why we should go into space’ on April 21, 2008, at George Washington University’s Morton Auditorium in Washington, DC.

Stephen Hawking gave an interview to Piers Morgan on “Good Morning Britain”, where he confirmed that he’ll be going to space on Richard Branson’s Virgin Galactic spaceship. Branson actually offered him the trip in 2015 for free, and Hawking says “since that day, I have never changed my mind.”

When the flight will be we don’t yet know. Virgin Galactic’s SpaceShipTwowas previously slated to launch at the end of 2017, but no hard date has been announced yet.

Hawking’s spaceflight will be an amazing feat for the 75-year-old scientist, known for his work in physics and cosmology, adding another chapter to an already remarkable life. When he was only 21, he was diagnosed with amyotrophic lateral sclerosis (ALS) also known as Lou Gehrig’s disease. This rare neurogenerative disease is deadly and Hawking was told he had 2 years to live. 

50+ years later, Hawking is still going strong (and going to space). Paralyzed and confined to a wheelchair, speaking through a specially-designed computer system since 1985, the scientist has achieved more than most do in a lifetime, not letting the debilitating disease slow him down.

Hawking has done groundbreaking work on black holes, discovering (along with James Bardeen and Brandon Carter) four laws of black holes mechanics.

His 1974 “Hawking radiation” theory that black holes are slowly evaporating due to particles robbing them of energy can still land him a Nobel Prize as recent research appears to prove it.

He has also done outstanding work on gravitational singularities, one-dimensional points that have infinite mass in infinitely tiny spaces. Cooperating with mathematician Roger Penrose, Hawking proved the existence of singularities and proposed key theorems on their origins. 

hawking nasa

Stephen Hawking, date unconfirmed but likely in 1990s. 

His other scientific achievements include pioneering work on cosmic inflation and the early state of the universe (which Hawking proposed had no time or beginning). 

Hawking is also famous for being one of the world’s most popular science educators, writing numerous books like the bestseller “A Brief History of Time,” which sold more than 10 million copies. 

How did Hawking, who also has been a professor of mathematics at University of Cambridge for the 30 years, thrive despite the illness? In an interview with Scientific American, ALS expert and professor of neurology Leo McCluskey, called Hawking “an outlier”. His case is exceptional and probably represents just a few percent of ALS patients. If Hawking developed the disease while still a teenager, it could be a “juvenile-onset” variant that progresses very slowly. He has also had great care.

How will Hawking fare in space? We don’t know the details of Virgin Galactic flight yet but Hawking seems quite enthusiastic:

“I can tell you what will make me happy, to travel in space. I thought no one would take me but Richard Branson has offered me a seat on Virgin Galactic and I said yes immediately.”

Source:http://bigthink.com

Stephen Hawking’s Beautiful Message For Anyone With Depression.

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Stephen Hawking has one of the greatest minds of our time. He is well known for his work in theoretical physics, and was born on January 8, 1942, (300 years after the death of Galileo) in Oxford, England. As a young child, he wanted to study mathematics, but once he began college, he studied Natural Sciences. Then, during his first year in Cambridge at the age of 21, Hawking began to have symptoms of ALS (amyotrophic lateral sclerosis). Doctors gave him two and a half years to live.

Now, at the age of 74, he continues to teach, research, and provide the world with beautiful messages. He says that his expectations were reduced to zero when he was given the ALS diagnosis. Ever since then, every aspect of his life has been a bonus.

One of the most brilliant minds did not allow these life challenges to stop him. He continued studying. Hawking has twelve honorary degrees. He has dedicated his life to finding answers about the universe, the Big Bang, creation and scientific theories.He cannot speak or move, bounded to a wheelchair, but he has found ways to inspire the world, encouraging us to find the mysticism in the stars. He says:

 “Remember to look up at the stars and not down at your feet. Never give up work. Work gives you meaning and purpose and life is empty without it. If you are lucky enough to find love, remember it is there and don’t throw it away.”

Recently during a lecture in January at the Royal Institute in London, Hawking compared black holes to depression, making it clear that neither the black holes or depression are impossible to escape. “The message of this lecture is that black holes ain’t as black as they are painted. They are not the eternal prisons they were once thought. Things can get out of a black hole both on the outside and possibly to another universe. So if you feel you are in a black hole, don’t give up; there’s a way out,” he said.

 When asked about his disabilities, he says: “The victim should have the right to end his life, if he wants. But I think it would be a great mistake. However bad life may seem, there is always something you can do, and succeed at. While there’s life, there is hope.” He continues with an inspiring message about disabilities:
“If you are disabled, it is probably not your fault, but it is no good blaming the world or expecting it to take pity on you. One has to have a positive attitude and must make the best of the situation that one finds oneself in; if one is physically disabled, one cannot afford to be psychologically disabled as well. In my opinion, one should concentrate on activities in which one’s physical disability will not present a serious handicap. I am afraid that Olympic Games for the disabled do not appeal to me, but it is easy for me to say that because I never liked athletics anyway. On the other hand, science is a very good area for disabled people because it goes on mainly in the mind. Of course, most kinds of experimental work are probably ruled out for most such people, but theoretical work is almost ideal.

My disabilities have not been a significant handicap in my field, which is theoretical physics. Indeed, they have helped me in a way by shielding me from lecturing and administrative work that I would otherwise have been involved in. I have managed, however, only because of the large amount of help I have received from my wife, children, colleagues and students. I find that people in general are very ready to help, but you should encourage them to feel that their efforts to aid you are worthwhile by doing as well as you possibly can.”

Stephen Hawking does not only encourage the scientific minds to pay attention, but inspires the rest of us to take notice that there is connection between the stars and each one of us. His disabilities have not stopped his curious mind and sense of wonder.

His daughter, Lucy, shared with the crowd at the lecture, “He has a very enviable wish to keep going and the ability to summon all his reserves, all his energy, all his mental focus and press them all into that goal of keeping going. But not just to keep going for the purposes of survival, but to transcend this by producing extraordinary work writing books, giving lectures, inspiring other people with neurodegenerative and other disabilities.”

Researchers develop unique model for studying ALS

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ALS researchers

The UF Health researchers that developed an ALS mouse model includes Dr. Laura P.W. Ranum, post-doctoral associate Dr. Yuanjing Liu; and graduate student Amrutha Pattamatta. Credit: University of Florida Health

University of Florida (UF) Health researchers have developed a unique mouse model that will allow researchers around the world to better study the genetic origins and potential treatments for a neurodegenerative brain disease that causes amyotrophic lateral sclerosis (ALS) and frontotemporal dementia.

The new mouse model is significant because it closely replicates the symptoms and gene expression patterns found in people who have the most common genetic cause of ALS and frontotemporal dementia. The findings are published online in the journal Neuron.

Having a mouse model that replicates how these two conditions affect nerve cells and pathways in the brain and spinal cord is crucial to understanding what triggers disease in people and for developing treatments, said Laura Ranum, PhD, director of the UF Center for NeuroGenetics, a faculty member of the UF Genetics Institute and a professor in the UF College of Medicine department of molecular genetics and microbiology.

The study’s lead author, Yuanjing Liu, PhD, a recent graduate of the UF interdisciplinary program in biomedical sciences, worked closely with graduate student Amrutha Pattamatta and other UF researchers to generate and characterize the mice. The team spent nearly four years developing the mouse model, which has an expansion mutation in the C9orf72 gene. This mutation is the most common genetic cause of ALS and accounts for up to 40 percent of all familial cases of the disease, according to The ALS Association.

ALS kills nerve cells that stretch from the brain to the spinal cord and from the spinal cord to muscles, causing muscle wasting, paralysis and death. An estimated 30,000 people in the United States have the disease at any given time and life expectancy is usually two to five years. This mutation is also a common cause of inherited dementia.

While other scientists have developed mouse models focusing on different ALS-related genes, the UF Health researchers are the first to cultivate one that focuses on the C9orf72 gene that closely mimics features of both ALS and frontotemporal dementia, including paralysis and dementia. The new mouse model will allow researchers to understand how the same genetic mutation causes paralysis in some patients and cognitive and behavioral problems in others, and how some people escape disease altogether. These mice showed the accumulation of problematic RNA and protein clumps suspected of helping the diseases to progress.

Because ALS and frontotemporal dementia belong to a genetically complex disease spectrum that isn’t easily studied in humans, the mouse models will enable researchers to tease apart exactly how the gene mutation causes disease. The C9orf72 gene produces at least eight different mutant products. Having the mouse model will help researchers understand which ones are the most important in terms of causing disease. It should also allow them to learn more about what takes place in a particular region of the brain where healthy cells exist next to ones that have died.

“I am excited because one of the two mutant RNAs produced by the mutation accumulates in neurons that are vulnerable to the disease and die. This gives us an important clue for future studies aimed at developing therapies for people,” Liu said.

Likewise, Ranum is intrigued by the 20 percent of the mice that have the mutated gene but do not develop ALS or frontotemporal dementia. Similarly, a subset of people who carry the C9orf72 mutation do not develop the disease. This suggests there is some protective element at work that, if understood, could be exploited to prevent disease onset, she said.

Ranum said her group is already making use of the new mouse model. That includes collaborations with private industry on research aimed at reversing or preventing the disease.

Scientists identify spark plug that ignites nerve cell demise in ALS

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myelin

False-colored scanning electron micrograph of myelinated nerve fibers.

Scientists from Harvard Medical School have identified a key instigator of nerve cell damage in people with amyotrophic lateral sclerosis, or ALS, a progressive and incurable neurodegenerative disorder.

Researchers say the findings of their study, published Aug. 5 in the journal Science, may lead to new therapies to halt the progression of the uniformly fatal disease that affects more than 30,000 Americans. One such treatment is already under development for testing in humans after the current study showed it stopped nerve cell damage in mice with ALS.

The onset of ALS, also known as Lou Gehrig’s disease, is marked by the gradual degradation and eventual death of neuronal axons, the slender projections on nerve cells that transmit signals from one cell to the next.

The HMS study reveals that the aberrant behavior of an enzyme called RIPK1 damages neuronal axons by disrupting the production of myelin, the soft gel-like substance enveloping axons to insulate them from injury.

“Our study not only elucidates the mechanism of axonal injury and death but also identifies a possible protective strategy to counter it by inhibiting the activity of RIPK1,” said the study’s senior investigator Junying Yuan, the Elizabeth D. Hay Professor of Cell Biology at HMS.

The new findings come on the heels of a series of pivotal discoveries made by Yuan and colleagues over the last decade revealing RIPK1 as a key regulator of inflammation and cell death. But up until now, scientists were unaware of its role in axonal demise and ALS.

Experiments conducted in mice and in human ALS cells reveal that when RIPK1 is out of control, it can spark axonal damage by setting off a chemical chain reaction that culminates in stripping the protective myelin off of axons and triggering axonal degeneration–the hallmark of ALS.

RIPK1, the researchers found, inflicts damage by directly attacking the body’s myelin production plants–nerve cells known as oligodendrocytes, which secrete the soft substance, rich in fat and protein that wraps around axons to support their function and shield them from damage.

Building on previous work from Yuan’s lab showing that the activity of RIPK1 could be blocked by a chemical called necrostatin-1, the research team tested how ALS cells in lab dishes would respond to the same treatment. Indeed, necrostatin-1 tamed the activity of RIPK1 in cells of mice genetically altered to develop ALS.

In a final set of experiments, the researchers used necrostatin-1 to treat mice with axonal damage and hind leg weakness, a telltale sign of axonal demise similar to the muscle weakness that occurs in the early stages of ALS in humans. Necrostatin-1 not only restored the myelin sheath and stopped axonal damage but also prevented limb weakness in animals treated with it.

Connecting the Dots

At the outset of their experiments, investigators homed in on a gene called optineurin (OPTN). Past research had revealed the presence of OPTN defects in people with both inherited and sporadic forms of ALS, but scientists were not sure whether and how OPTN was involved in the development of the disease. To find out, researchers created mice genetically altered to lack OPTN. Examining spinal cord cells under a microscope, the scientists noticed that the axons of mice missing the OPTN gene were swollen, inflamed and far fewer in number, compared with spinal cord cells obtained from mice with the OPTN gene. These axons also bore signs of myelin degradation. Strikingly, the researchers noticed the same signs of axonal demise in spinal cord cells obtained from human patients with ALS. Mice with OPTN deficiency also exhibited loss of strength in their hind legs. Further experiments revealed that lack of OPTN was particularly harmful to myelin-secreting cells. Thus, the researchers concluded, OPTN deficiency was directly incapacitating the nervous system’s myelin factories. But one question remained: How did the absence of OPTN damage these cells?

A Smoking Gun

Looking for the presence of chemicals commonly seen during inflammation and cell death, the researchers noticed abnormally high levels of RIPK1–a known promoter of cell death–in spinal cord cells from mice lacking OPTN. Moreover, the scientists observed traces of other damaging chemicals often recruited by RIPK1 to kill cells.

“It was as if we saw the chemical footprints of cell death left behind by RIPK1 and its recruits,” Yuan said.

That observation, Yuan added, was the smoking gun linking RIPK1’s misbehavior to OPTN deficiency. In other words, researchers said, when functioning properly, the OPTN gene appears to regulate the behavior of RIPK1 by ensuring its levels are kept in check, that it is broken down fast and that it is cleared out of cells in a timely fashion. In the absence of such oversight, however, RIPK1 appears to get out of control and cause mischief.

In a closing set of experiments, the researchers examined neurons obtained from mice with the most common inherited form of ALS, one caused by mutations in a gene called SOD1. Indeed, RIPK1 levels were elevated in those cells too. Thus, the investigators said, OPTN may not be the sole gene regulating RIPK1’s behavior. Instead, RIPK1 appears to fuel axonal damage across various forms of inherited and acquired forms of ALS.

The findings suggest that RIPK1 may be involved in a range of other neurodegenerative diseases marked by axonal damage, including multiple sclerosis, certain forms of spinal muscular atrophy and even Alzheimer’s disease.

The Harvard Office of Technology Development (OTD) and collaborating institutions have developed a patent portfolio for RIPK1 modulating compounds. Harvard OTD has licensed the patent to a biotechnology company.

New Gene Mutations Discovered in ALS

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Researchers have made more headway in zeroing in on the genetic drivers behind amyotrophic lateral sclerosis (ALS).

A team led by investigators at the National Institutes of Health’s National Institute on Aging have identified mutations in the Matrin 3 gene, located on chromosome 5, and revealed that MATR3, an RNA- and DNA-binding protein, interacts with TDP-43, a protein linked to ALS.

“The identification of this gene mutation gives us another target to explore in the pathogenesis of this disease,” said senior author Bryan J. Traynor, MD, PhD, from the National Institute of Aging Laboratory of Neurogenetics, in a press release. “It also provides additional evidence that some disruption in RNA metabolism, an essential process within all cells, is involved in neuron death in ALS.”

The research was published online March 30 in Nature Neuroscience.

Using exome sequencing, Janel O. Johnson, PhD, from the Neuromuscular Diseases Research Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, and colleagues found 2 previously unknown heterozygous missense variants in MATR3 in a family of European ancestry, several members of which had been diagnosed with ALS and dementia. Neither of these variants was present in population polymorphism databases or in the Human Gene Diversity Panel of 2102 chromosomes screened in the neurogenetics laboratory. The MATR3 variant was also not present in another 5190 neurologically normal subjects genotyped in the laboratory.

A MATR3 mutation was previously reported as the cause of autosomal-dominant, distal asymmetrical myopathy with vocal cord paralysis in a large multigenerational family. In light of the new genetic findings, the researchers decided to reevaluate this family.

They found that affected individuals developed progressive respiratory failure resulting in death, typically after 15 years. Pathologically brisk knee reflexes, indicative of upper motor neuron lesions, were present in 4 of 6 patients examined. All cases displayed a “split hand” pattern of weakness suggestive of a lesion in the anterior horn of the cervical spinal cord, a sign commonly observed in patients with ALS.
“These clinical findings supported reclassification of this condition as slowly progressive ALS, and the presence of upper motor neuron signs in the form of brisk reflexes rule out myopathy as the only cause of disease in this family,” the authors write.

Additional Cases

To determine the frequency of MATR3 mutations as a cause of ALS, the researchers examined exome sequence data using DNA from 108 additional familial ALS cases (including 6 Canadians, 14 Germans, 9 Israelis, 32 Italians, and 47 Americans) who were negative for mutations in known ALS-associated genes. The authors found a variant in MTR3 in a 66-year-old patient diagnosed with familial ALS and in an individual diagnosed with sporadic disease. Again, neither mutation was present in population polymorphism databases or in the Human Gene Diversity Panel.

The investigation revealed an interaction between the MATR3 protein and the TDP-43 protein, an RNA-binding protein whose mutation is known to cause ALS.

The mutation discovery should allow more complete mapping of the cellular pathways underlying ALS, the study authors said. The new data, they write, “identify mutations of the MATR3 gene as a rare cause of familial ALS and broaden the phenotype associated with this gene beyond the previously reported distal myopathy. This,” they add, “provides further insight into the importance of RNA metabolism in this fatal neurodegenerative disease.”

Characterized by progressive paralysis and respiratory failure leading to death, ALS kills about 6000 Americans each year. About 10% of people with ALS have a directly inherited form of the disease. The genetic etiology of two thirds of the familial form of ALS and 11% of the more common sporadic form of the disease are known.

Clinical Trials of Therapies for Amyotrophic Lateral Sclerosis

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This Viewpoint discusses amyotrophic lateral sclerosis as a syndrome rather than a single disease that requires varied diagnostic and therapeutic approaches.

The French neurologist Jean-Marie Charcot (1825-1893) is acclaimed for his studies on the motor system and unifying previously disparate entities into 1 disorder, amyotrophic lateral sclerosis (ALS). His careful work correlating neurological signs with anatomy led to the concept that a spectrum of neurological disorders, including progressive muscular atrophy, progressive bulbar palsy, and primary lateral sclerosis, represented a single entity, ALS. Charcot summarized his ideas in a frequently cited review in 1874 that has dominated medical nosology for 140 years.1.

http://archneur.jamanetwork.com/Mobile/article.aspx?articleID=2279880&utm_source=facebook&utm_medium=social_jamaneur&utm_campaign=article_alert&utm_content=automated

‘INDIVIDUALIZED’ THERAPY FOR THE BRAIN TARGETS SPECIFIC GENE MUTATIONS CAUSING DEMENTIA AND ALS.

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Stem cell-based approach manipulates brain cells in test tube studies

Johns Hopkins scientists have developed new drugs that — at least in a laboratory dish — appear to halt the brain-destroying impact of a genetic mutation at work in some forms of two incurable diseases, amyotrophic lateral sclerosis (ALS) and dementia.

They made the finding by using neurons they created from stem cells known as induced pluripotent stem cells (iPS cells), which are derived from the skin of people with ALS who have a gene mutation that interferes with the process of making proteins needed for normal neuron function.

“Efforts to treat neurodegenerative diseases have the highest failure rate for all clinical trials,” saysJeffrey D. Rothstein, M.D., Ph.D., a professor of neurology and neuroscience at the Johns Hopkins University School of Medicine and leader of the research described online in the journal Neuron. “But with this iPS technology, we think we can target an exact subset of patients with a specific mutation and succeed. It’s individualized brain therapy, just the sort of thing that has been done in cancer, but not yet in neurology.”

Scientists in 2011 discovered that more than 40 percent of patients with an inherited form of ALS and at least 10 percent of patients with the non-inherited sporadic form have a mutation in the C9ORF72 gene. The mutation also occurs very often in people with frontotemporal dementia, the second-most-common form of dementia after Alzheimer’s disease. The same research appeared to explain why some people develop both ALS and the dementia simultaneously and that, in some families, one sibling might develop ALS while another might develop dementia.

In the C9ORF72 gene of a normal person, there are up to 30 repeats of a series of six DNA letters (GGGGCC); but in people with the genetic glitch, the string can be repeated thousands of times. Rothstein, who is also director of the Johns Hopkins Brain Science Institute and the Robert Packard Center for ALS Research, used his large bank of iPS cell lines from ALS patients to identify several with the C9ORF72 mutation, then experimented with them to figure out the mechanism by which the “repeats” were causing the brain cell death characteristic of ALS.

In a series of experiments, Rothstein says, they discovered that in iPS neurons with the mutation, the process of using the DNA blueprint to make RNA and then produce protein is disrupted. Normally, RNA-binding proteins facilitate the production of RNA. Instead, in the iPS neurons with the C9ORF72 mutation, the RNA made from the repeating GGGGCC strings was bunching up, gumming up the works by acting like flypaper and grabbing hold of the extremely important RNA binding proteins, including one known as ADARB2,  needed for the proper production of many other cellular RNAs. Overall, the C9ORF72 mutation made the cell produce abnormal amounts of many other normal RNAs and made the cells very sensitive to stress.

To counter this effect, the researchers developed a number of chemical compounds targeting the problem. This compound behaved like a coating that matches up to the GGGGCC repeats like velcro, keeping the flypaper-like repeats from attracting the bait, allowing the RNA-binding protein to properly do its job.

Rothstein says Isis Pharmaceuticals helped develop many of the studied compounds and, by working closely with the Johns Hopkins teams, could begin testing it in human ALS patients with the C9ORF72 mutation in the next several years. In collaboration with the National Institutes of Health, plans are already underway to begin to identify a group of patients with the C9ORF72 mutation for future research.

Rita Sattler, Ph.D., an assistant professor of neurology at Johns Hopkins and the co-investigator of the study, says without iPS technology, the team would have had a difficult time studying the C9ORF72 mutation. “Typically, researchers engineer rodents with mutations that mimic the human glitches they are trying to research and then study them,” she says. “But the nature of the multiple repeats made that nearly impossible.” The iPS cells did the job just as well or even better than an animal model, Sattler says, in part because the experiments could be done using human cells.

“An iPS cell line can be used effectively and rapidly to understand disease mechanisms and as a tool for therapy development,” Rothstein adds. “Now we need to see if our findings translate into a valuable treatment for humans.”

The researchers also analyzed brain tissue from people with the C9ORF72 mutation who died of ALS. They saw evidence of this bunching up and found that the many genes that were altered as a consequence of this mutation in the iPS cells were also abnormal in the brain tissue, thereby showing that iPS cells can be a faithful tool to study the human disease and discover effective therapies.

In the future, the scientists will look at cerebral spinal fluid from ALS patients with the C9ORF72 mutation, searching for proteins that were found both in the fluid and the iPS cells. These may pave the way to develop markers that can be studied by clinicians to see if the treatment is working once the drug therapy is moved to clinical trials.

ALS, sometimes known as Lou Gehrig’s disease, named for the Yankee baseball great who died from it, destroys 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, Rothstein notes.

Frontotemporal dementia.

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  • Frontotemporal dementia refers to a diverse group of conditions that collectively are a major cause of young onset dementia
  • Frontotemporal dementia produces selective brain atrophy involving the frontal and temporal lobes, requiring brain magnetic resonance imaging for accurate diagnosis
  • Clinically, these diseases present chiefly as progressive aphasia or as disintegration of personality and behaviour that may be misdiagnosed as a psychiatric disorder
  • Up to around a quarter of cases arise from dominant mutations in one of three major causative genes
  • Frontotemporal dementia is commonly associated with other neurological impairment, in particular parkinsonism or motor neurone disease
  • Treatment remains supportive, but patients and families need extensive counselling, future planning, and involvement of social and mental health services

 

Source: BMJ