RASCALS 5K POSTPONED :(

Due to unforeseen scheduling conflicts, the RASCALS Foundation regrets to announce that its 3rd Annual 5K Walk/Run on May 4th has been postponed to a later date.

We are, of course, very disappointed and sincerely apologize for any inconvenience to our volunteer race staff and participants.

The decision was not as easy one.

Reimbursements will be processed as soon as possible, and a new date for the 5K will be announced in the near future.

Thank you for your understanding and continued support.

Above and Beyond: Jon Imber

Film Review: ‘Jon Imber’s Left Hand’ an Extraordinary Documentary

By Daniel Kany for the Portland Press Herald, April 5, 2014 •

Jon Imber, who is fighting amyotrophic lateral sclerosis, also known as Lou Gehrig’s disease, was photographed in his studio last fall for a profile by Telegram arts writer Bob Keyes. Telegram file photos by Gregory Rec/Staff Photographer

Jon Imber, who is fighting ALS, was photographed in his studio last fall for a profile by Telegram arts writer Bob Keyes.
Telegram file photos by Gregory Rec/Staff Photographer

“Jon Imber’s Left Hand” opens with the 63-year-old artist standing in front of a canvas with two helpers. He can hardly move and barely hold a brush. His speech has withered to grunts. The scene was shot on Feb. 10, 2014.

In the fall of 2012, Imber was diagnosed with amyotrophic lateral sclerosis, or ALS, the fatal degenerative condition also known as Lou Gehrig’s disease.

The next scene shows a robust and articulate Imber talking about art. He is friendly, forceful and witty. Fully aware of his prognosis but not yet seriously limited by the disease, Imber reveals his destiny: “I have just months.”

Months to live? Or months to paint?

This is the question underlying director Richard Kane’s bittersweet and deeply moving film, which premiered last week during the Maine Jewish Film Festival and is the latest in the superb Maine Masters series produced by the Union of Maine Visual Artists.

“Jon Imber’s Left Hand” picks up at the start of what Imber calls “my ALS summer.” It is a story about the artist and his wife, the painter Jill Hoy. The pair for decades have been key members of the Stonington and Maine painting communities. While Imber is the object of the film, Hoy is its true subject. We see Imber lean more and more on his loving wife. And while we watch him become a prisoner of his own failing body, it is Hoy’s heart that we feel breaking.

For Imber, the diagnosis is an urgent challenge: It motivates him to spend every last moment living.

And for Imber, art is life.

The film features a painting session in which ALS has forced Imber to switch to his left hand. Almost defiantly, Imber’s two-inch house brush glides with drippy-wet paint, boldly swishing and diving over a tall, slender canvas. Within minutes, the painting is beautiful – too beautiful.

So Imber flips over the canvas and goes back to work.

A recent portrait by Stonington painter Jon Imber.

A recent portrait by Stonington painter Jon Imber.

This reveals Imber’s goal, not to accurately paint the vase of flowers before him, but to make a good painting. For him, a satisfying outcome needs to resolve tension. Anything facile is too easy to be interesting, and this is why Imber’s ALS-forced switch leads to such surprisingly strong work.

While many painters are not used to people looking over their shoulder as they work, Imber, an extroverted teacher, is accustomed to an audience and to thinking out loud. This makes “Jon Imber’s Left Hand” an extraordinary document about both ALS and the artistic process.

Imber is a natural narrator, so Kane lets his voice set the pace of the film. Gallery reception conversations are buoyant and jaunty. Imber’s comments to crowds are funny and forceful but punctuated with time to look. And his intimate conversations are generous and patient.

The film exudes the artist’s credo: To paint is to live

Despite the insightful comments from an impressive cadre of colleagues, critics and curators, Kane lets the key questions and conclusions come from Hoy and Imber. Deep into his ALS, Imber is more dedicated to being a parent than painting (their son is a student at Bates College). But Hoy is persuasive when she finally lets the tears flow, saying “painting is his life.” She believes that, when he can no longer paint, Imber will depart. So Hoy does everything possible to keep him painting.

Imber knows his legacy will live on through his family and among the students he taught over 27 years at Harvard. And it will ride the ages in the scores of paintings we see throughout the film. Moreover, Imber has the measure of his post-diagnosis work: His newest abstract landscapes are as strong as anything he ever painted. And he knows it.

Kane shows Imber talking through his relationships with powerful figures such as his father and his teacher Philip Guston. (Despite Guston’s oversized role in Imber’s life, the key unspoken comparison of the film is with Willem deKooning both because of his approach to painting and the famous effect of Alzheimer’s on his career.)

Chatting over family photos, Imber claims his Judaism had little to do with his life and work, yet again the insightful Hoy persuasively disagrees. While this poignant scene binds the film brightly to the Maine Jewish Film Festival, it’s a family moment with which everyone can identify: It’s often easier, after all, for others to see our family in us.

The film closes with a return to the scene shot last month in Somerville with Imber heroically struggling against his failing body to paint – to live.

A masterpiece of intimacy in the face of tragedy, “Jon Imber’s Left Hand” is an extraordinary accomplishment in film. It is the eulogizing of the creative force and artistic life of one of America’s leading painters – in his own vibrant voice.

#

Freelance writer Daniel Kany is an art historian who lives in Cumberland. He can be contacted at: dankany@gmail.com

# # #

The Robert A. Stehlin Campaign for ALS (R.A.S.C.A.L.S.) is an all-volunteer 501(c)(3) charity. 100% of all funds raised go to building awareness, treatment research and development, plus ALS family assistance. There are no administrative costs.

Contributions are tax-deductible.

You may also be interested in visiting the RASCALS Store.

The material presented here is for informational purposes only and should not be construed as medical advice, or relied upon as a substitute for medical advice from a health care provider.

Why is Lou Gehrig’s Disease Closely Related to Veterans?

gulf-war-syndrome

By S. E. Smith at Care2, April 11, 2014 •

Something is eating away at the nervous systems of military veterans like Thomas Corbett, Jeff Long, and Mike White. It started with some tingling and numbness, difficulty walking and poor hand coordination, and it progressed to stumbling and an increasingly limited range of motion.

It’s called amyotrophic lateral sclerosis (ALS), or Lou Gehrig’s disease, after the baseball player who made it famous (though he’s not the only famous patient — Stephen Hawking also has the condition). ALS attacks the motor neurons in the brain and spinal cord responsible for controlling muscle movement, slowly paralyzing patients over time.

As the disease progresses, they start to need assistance walking, finally needing a wheelchair for mobility. Eventually, patients need assistance with even basic daily tasks, including grooming, using the bathroom and eating. Many patients wind up on ventilators because they are no longer able to breathe independently, with pneumonia and other lung infections being a common cause of death as their immune systems decline and their limited mobility makes it challenging to fight off infections.

Depending on the progression of the disease and the care the patient receives, it can move quickly and ruthlessly, or more slowly. And while a very small percentage of cases appear to have a genetic component, others appear out of the blue.

Still, none of this explain why military veterans, particularly those who served in the First Gulf War, are twice as likely to get it when compared to the rest of the population. Since 2008, the Veterans Administration has recognized that there’s a clear link between ALS and military service, and the agency considers it to be a service-connected disability, meaning that service either causes or exacerbates it. This makes veterans eligible for comprehensive assistance from the VA, but it still doesn’t address the root question: where are all these cases of ALS coming from?

An estimated 2,000 veterans live with ALS today, while as many as 30,000 people overall have the disease. It’s an extremely common motor neuron disease, making it a prime subject for research and development, yet scientists have been unable to pin down specific environmental causes. One study found a possible link between ALS and recreational athletics — the condition is seen in soccer and NFL players, for example, and Iraq veterans tend to have injuries similar to those observed in athletes. It could also be environmental, related to chemical exposure or other factors.

Most likely, it’s a combination of factors that causes proteins to go rogue and start attacking motor neurons. Therapy for ALS is focused on developing treatments that target these proteins, or take another tack, using stem cells to replace damaged motor neurons. While these treatments in development are good news for current patients, everyone is still waiting for the answer to the more fundamental question about the origins of ALS, and whether it could be prevented or mitigated.

Numerous illnesses appear to have mysterious connections to service in the Gulf, including Chronic Fatigue Syndrome and so-called “Gulf War Syndrome.” This could be due to chemical weapons and other toxins that may have been present in the environment, or it could have been caused by the military’s own materials. It’s possible that even the vaccines used might have created problems for servicemembers. Whatever’s causing the increase in neurological diseases, among others, hasn’t been narrowed down, but it’s very real for the veterans struggling with these conditions.

Can researchers and the VA pin down the origins of ALS? It might be important not just for veterans but for civilians, especially those in war zones who may be exposed to the same environmental factors that veterans interact with during their service.

# # #

The Robert A. Stehlin Campaign for ALS (R.A.S.C.A.L.S.) is an all-volunteer 501(c)(3) charity. 100% of all funds raised go to building awareness, treatment research and development, plus ALS family assistance. There are no administrative costs.

Contributions are tax-deductible.

You may also be interested in visiting the RASCALS Store.

The material presented here is for informational purposes only and should not be construed as medical advice, or relied upon as a substitute for medical advice from a health care provider.

Study Shows Neuralstem Cells Transplanted Into Brain Significantly Improve Post-Stroke Symptoms in Rats

ROCKVILLE, Maryland, March 28, 2014 — Neuralstem, Inc. announced that a study published in the peer-reviewed journal, PLOS ONE, showed that ischemic-stroke rats transplanted with Neuralstem’s NSI-566 stem cells in the brain experienced functional improvements. Furthermore, the grafts both survived and differentiated into neurons. These findings further validate the application of the cells for transplantation therapy in ischemic stroke. The researchers concluded that the NSI-566 cells are potent cell donors for transplantation therapy to treat paralysis in stroke patients

In the study, “Behavioral and Histopathological Assessment of Adult Ischemic Rat Brains after Intracerebral Transplantation of NSI-566RSC Cell Lines,” researchers also reported that improvements appeared to be dose dependent, with rats receiving higher doses of the cells functioning significantly better than those with low-dose or sham therapies. Rats transplanted with 10,000 or 20,000 cells/ul revealed statistically significant better treatment effects of motor recovery and neurological test improvement than rats receiving 5,000 cells/ul. Moreover, improvements in the higher dose groups continued over the course of the study.

Neuralstem is currently conducting a Phase II NSI-566 clinical trial in amyotrophic lateral sclerosis (ALS or Lou Gehrig’s disease) in three U.S. sites, as well as a Phase I/II to treat post-stroke motor deficit in China, through its wholly-owned subsidiary, Neuralstem China. The company also has been approved by the FDA to commence a trial with the same cells to treat chronic spinal cord injury.

“Repairing damage from stroke is a major unmet clinical need,” said study lead author Cesar V. Borlongan, PhD, Professor, Department of Neurosurgery, Morsani College of Medicine and Director of University of South Florida’s Center of Excellence for Aging and Brain Repair. “Laboratory testing and limited human clinical trials, using an increasing diversity of cell sources for transplantation, indicate that transplanting human-derived neural stem cells into stroke victims is safe and effective. Although the mechanisms of action for stem cell therapy are not clear, our study suggests a potential therapeutic value of intracerebral dosing of cells from the NSI-566RSC cell line in ischemic stroke.”

“We believe there are many indications we will address with transplantation of cells directly into the brain,” said Karl Johe, Ph.D, Neuralstem’s Chairman of the Board and Chief Scientific Officer. “We are pleased to see the peer review publication of this important proof of principle data in stroke. This compelling data played an important role in our initiating the stroke trial in China. We wish to thank Dr. Borlongan, and his entire team at the USF Center of Excellence for Aging and Brain Repair, for their efforts in conducting this ground-breaking study.”

About the Study

In a study of 40 rats, all received strokes in the brain via cerebral artery occlusion, a well-established stroke model. Seven-days post stroke, the animals were divided into four groups. Group A received no stem cells. Groups B and C received 5,000 and 10,000 NSI-566 cells/ul, respectively and group D received 20,000 cells/ul. All groups had displayed typical stroke-induced behavioral deficits after stroke and prior to transplantation. Seven days after transplantation, the animals were tested again at intervals that continued throughout the duration of the study, 56 days post-transplantation.

Researchers, who were blinded as to which rats they were working with, reported significantly better recovery of motor and neurological tests in animals transplanted with high doses, than with those that had received the lower dose or no stem cells at all. Additionally, the high-dose rats showed a better and stable improvement over time.

About Neuralstem

Neuralstem’s patented technology enables the production of neural stem cells of the brain and spinal cord in commercial quantities, and the ability to control the differentiation of these cells constitutively into mature, physiologically relevant human neurons and glial cells. Neuralstem’s NSI-566 spinal cord-derived stem cell therapy is in Phase II clinical trials for amyotrophic lateral sclerosis (ALS), often referred to as Lou Gehrig’s disease. Neuralstem has been awarded orphan status designation by the FDA for its ALS cell therapy.

In addition to ALS, the company is also targeting major central nervous system conditions with its NSI-566 cell therapy platform, including spinal cord injury and ischemic stroke. The company has received FDA approval to commence a Phase I safety trial in chronic spinal cord injury.

Neuralstem also maintains the ability to generate stable human neural stem cell lines suitable for systematic screening of large chemical libraries. Through this proprietary screening technology, Neuralstem has discovered and patented compounds that may stimulate the brain’s capacity to generate neurons, possibly reversing pathologies associated with certain central nervous system conditions. The company has completed a Phase I safety trial evaluating NSI-189, its first neurogenic small molecule product candidate, for the treatment of major depressive disorder (MDD). Additional indications might include traumatic brain injury (TBI), Alzheimer’s disease, and post-traumatic stress disorder (PTSD).

For more information, please visit www.neuralstem.com or connect on Twitter, Facebook, and LinkedIn.

Cautionary Statement Regarding Forward Looking Information:

This news release may contain forward-looking statements made pursuant to the “safe harbor” provisions of the Private Securities Litigation Reform Act of 1995. Investors are cautioned that such forward-looking statements in this press release regarding potential applications of Neuralstem’s technologies constitute forward-looking statements that involve risks and uncertainties, including, without limitation, risks inherent in the development and commercialization of potential products, uncertainty of clinical trial results or regulatory approvals or clearances, need for future capital, dependence upon collaborators and maintenance of our intellectual property rights. Actual results may differ materially from the results anticipated in these forward-looking statements. Additional information on potential factors that could affect our results and other risks and uncertainties are detailed from time to time in Neuralstem’s periodic reports, including the annual report on Form 10-K for the year ended December 31, 2013.

SOURCE: Neuralstem, Inc.

CONTACT: Plant Communications – Media Relations, Deanne Eagle, 917.837.5866;

MDC Group – Investor Relations, Susan Roush, 747.222.7012;

MDC Group – Investor Relations, David Castaneda, 414.351.9758

# # #

The Robert A. Stehlin Campaign for ALS (R.A.S.C.A.L.S.) is an all-volunteer 501(c)(3) charity. 100% of all funds raised go to building awareness, treatment research and development, plus ALS family assistance. There are no administrative costs.

Contributions are tax-deductible.

You may also be interested in visiting the RASCALS Store.

The material presented here is for informational purposes only and should not be construed as medical advice, or relied upon as a substitute for medical advice from a health care provider.

BrainStorm and Mass General Sign Definitive Agreement for ALS Clinical Trial

New York & Petach Tikvah, Israel, March 25, 2014 – BrainStorm Cell Therapeutics, a leading developer of adult stem cell technologies for neurodegenerative diseases, announced today that it has signed a definitive agreement with the Massachusetts General Hospital (MGH) in Boston, MA to conduct a Phase II clinical trial of NurOwn™ in amyotrophic lateral sclerosis (ALS), pending FDA and Institutional Review Board approvals. The other two clinical sites slated for the multi-center trial are the University of Massachusetts Memorial (UMass) Hospital and Mayo Clinic. Dana Farber Cancer Institute’s Connell and O’Reilly Cell Manipulation Core Facility will manufacture the NurOwn cells for MGH and UMass Hospital.

Ali

Rasheda Ali visits the BrainStorm Cell Therapeutics cleanroom at the Hadassah Medical Center in Jerusalem, August 2012.

“We are excited to be taking the final steps towards FDA approval and the U.S. trial launch,” said Chaim Lebovits, President of BrainStorm. “It is a privilege to be collaborating with Professor Merit Cudkowicz, Chair of Neurology at Massachusetts General Hospital, Professor of Neurology at Harvard Medical School, and leading expert in the field.”

“It is encouraging that stem cell treatments are now in development for people with ALS, and we are eager to begin this trial with BrainStorm’s unique approach,” commented Merit Cudkowicz, M.D., Principal Investigator at MGH.

About Massachusetts General Hospital

Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of more than $775 million and major research centers in AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, reproductive biology, systems biology, transplantation biology and photomedicine.

About BrainStorm Cell Therapeutics, Inc.

BrainStorm Cell Therapeutics Inc. is a biotechnology company engaged in the development of first-of-its-kind adult stem cell therapies derived from autologous bone marrow cells for the treatment of neurodegenerative diseases. The Company holds the rights to develop and commercialize its NurOwn technology through an exclusive, worldwide licensing agreement with Ramot, the technology transfer company of Tel Aviv University.

For more information, visit the company’s website at www.brainstorm-cell.com.

Safe Harbor Statement

Statements in this announcement other than historical data and information constitute “forward-looking statements” and involve risks and uncertainties that could cause BrainStorm Cell Therapeutics Inc.’s actual results to differ materially from those stated or implied by such forward-looking statements. Terms and phrases such as “may”, “should”, “would”, “could”, “will”, “expect”, “likely”, “believe”, “plan”, “estimate”, “predict”, “potential”,  and similar terms and phrases are intended to identify these forward-looking statements.  The potential risks and uncertainties include, without limitation, risks associated with BrainStorm’s limited operating history, history of losses; minimal working capital, dependence on its license to Ramot’s technology; ability to adequately protect the technology; dependence on key executives and on its scientific consultants; ability to obtain required regulatory approvals; and other factors detailed in BrainStorm’s annual report on Form 10-K and quarterly reports on Form 10-Q available at http://www.sec.gov.  These factors should be considered carefully, and readers should not place undue reliance on BrainStorm’s forward-looking statements.  The forward-looking statements contained in this press release are based on the beliefs, expectations and opinions of management as of the date of this press release. We do not assume any obligation to update forward-looking statements to reflect actual results or assumptions if circumstances or management’s beliefs, expectations or opinions should change, unless otherwise required by law. Although we believe that the expectations reflected in the forward-looking statements are reasonable, we cannot guarantee future results, levels of activity, performance or achievements.

Contacts:
BrainStorm Cell Therapeutics Inc. (OTC.QB: BCLI)
Mr. Chaim Lebovits, President
Phone: +972-3-9236384
info@brainstorm-cell.com
www.brainstorm-cell.com

# # #

The Robert A. Stehlin Campaign for ALS (R.A.S.C.A.L.S.) is an all-volunteer 501(c)(3) charity. 100% of all funds raised go to building awareness, treatment research and development, plus ALS family assistance. There are no administrative costs.

Contributions are tax-deductible.

You may also be interested in visiting the RASCALS Store.

The material presented here is for informational purposes only and should not be construed as medical advice, or relied upon as a substitute for medical advice from a health care provider.

ALS Researchers Uncover New Insights into Motor Neuron Death

By Susan Ardizzoni for BioNews Texas, March 31, 2014 •

Current research at The Institute at Nationwide Children’s Hospital has revealed information about a key player in motor neuron death in Amyotrophic lateral sclerosis (ALS) otherwise known as Lou Gehrig’s disease.  The researchers believe this to be a key step in developing a treatment.

shutterstock_125891597-376x400ALS involves a cascade of cellular and inflammatory events that weakens and kill motor neurons in the brain and spinal column.  The motor neuron destruction is a complex process that involves cells that normally protect neurons from harm.  These motor neurons control the function of muscles throughout the body.  As the motor neurons die, muscles begin to weaken.  Individuals with ALS eventually lose their ability to move, and with further progression they are unable to breathe on their own.  Within 3 to 5 years of onset, most ALS patients die from respiratory failure.

Researchers took a look at a protein that is involved in transcriptional regulation known as nuclear factor-kappa B (NF-?B).  This protein is involved with the neuro-inflammatory response that is common in ALS, and it has also been linked to cancer and a number of other inflammatory and autoimmune diseases.

The study examined ALS progression in mice where NF-?B was inhibited in astrocytes and microglia.  These two cell types are the first and main form of defense against pathogens in the brain and spinal column.  According to Brian Kaspar, MD, a principal investigator in the Center for Gene Therapy at Nationwide Children’s and senior author of the new study,  inhibiting NF-kB in microglia decreased ALS progression by 47 percent. “ The field has identified different cell types in addition to motor neurons involved in this disease, so one of our approaches was to find out what weapons these cells might be using to kill motor neurons.  And our findings suggest that the microglia utilize an NF-kB-mediated inflammatory response as one of its weapons.”

Researchers report that inhibiting NF-kB in astrocytes had no effect on ALS progression so the search for weapons that astrocytes use against motor neurons still continues.  How or why NF-kB causes microglia to turn into neuron-killing agents still remains a mystery, however the current study moves researchers closer to finding therapy for ALS.

Current ALS research is focused in two directions.  One path is trying to determine the trigger that leads to ALS onset.  The other path is trying to understand the process that leads to ALS progression.  It is known that changes in motor neurons leads to ALS onset, however disease progression appears to be determined by alterations to astrocytes, microglia and oligodendrocytes.  Most cases of ALS have no family ties to the disease, however some cases are hereditary.  Due to the complexity of ALS and the lack of familiar tie, screening before onset is practically impossible.

According to Kaspar, “Focusing on stopping the changes that occur in astrocytes and microglia has clinical relevance because most people don’t know they’re getting ALS.  We have identified a pathway in microglia that may be targeted to ultimately slow disease progression in ALS and are exploring potential therapeutic strategies and may have broader implications for diseases such as Alzheimer’s and Parkinson’s Disease amongst others.”

# # #

The Robert A. Stehlin Campaign for ALS (R.A.S.C.A.L.S.) is an all-volunteer 501(c)(3) charity. 100% of all funds raised go to building awareness, treatment research and development, plus ALS family assistance. There are no administrative costs.

Contributions are tax-deductible.

You may also be interested in visiting the RASCALS Store.

The material presented here is for informational purposes only and should not be construed as medical advice, or relied upon as a substitute for medical advice from a health care provider.

 

The RASCALS Foundation Announces Higher Education Scholarships for 2014

blue tassel

The RASCALS Foundation is pleased to announce that it is once again offering  the 2014 Higher Education Scholarship Program to assist families affected by ALS. We would like to acknowledge and thank our newest partner Helping Hands for ALS, a student group associated with John Burroughs High School for their generous participation in making these important awards possible.

The scholarships will be available nationwide to the first 100 qualifying applicants. The program, guidelines and application process will begin today, March 20, 2014. To request an application packet, simply email MichaelBrand314@gmail.com  or call 314-477-8120.

You may also check the website  for guideline information to be posted in a dedicated 2014 Scholarship section.

# # #

The Robert A. Stehlin Campaign for ALS (R.A.S.C.A.L.S.) is an all-volunteer 501(c)(3) charity. 100% of all funds raised go to building awareness, treatment research and development, plus ALS family assistance. There are no administrative costs.

Contributions are tax-deductible.

You may also be interested in visiting the RASCALS Store.

The material presented here is for informational purposes only and should not be construed as medical advice, or relied upon as a substitute for medical advice from a health care provider.

ALS Toxicity Reduced in Animal Models

Amyotrophic lateral sclerosis (ALS), better known as Lou Gehrig’s disease, is a devastating illness that gradually robs sufferers of muscle strength and eventually causes a lethal, full-body paralysis. The only drug available to treat the disease extends life spans by a meager three months on average.

In a new study published in Nature Genetics, University of Pennsylvania researchers and colleagues have made inroads into the mechanism by which ALS acts. Working with a powerful fruit fly model of the disease, they found a way of reducing disease toxicity that slows the dysfunction of neurons and showing that a parallel mechanism can reduce toxicity in mammalian cells. Their discoveries offer the possibility of a new strategy for treating ALS.

The senior author of the study is Nancy Bonini, a professor in the Department of Biology in Penn’s School of Arts and Sciences. Contributors from her lab include Hyung-Jun Kim, Leeanne McGurk and Ross Weber. They partnered on the work with long-time collaborators from Penn’s Perelman School of Medicine, John Trojanowski and Virginia M-Y Lee. Additional co-authors included Alya Raphael and Aaron Gitler of Stanford University and Eva S. LaDow and Steven Finkbeiner of the Gladstone Institute of Neurological Disease.

Recent years have seen an uptick in scientific understanding of the genetic roots of ALS.

“There’s been an explosion over the last five-plus years in the identification of genes that contribute to genetically inherited ALS,” Bonini said.

One of the key genes that has come to light as playing a role in the disease is called TDP-43, which binds to RNA and has been found to aggregate abnormally in the cytoplasm of patients with ALS.

Previous studies led by Gitler and Bonini, working with colleagues including Trojanowski and Lee, had found that TDP-43 interacts with a gene called ataxin-2.

“That became very interesting to us because ataxin-2 on its own is a gene whose mutations cause human degenerative disease,” Bonini said.

Given the strong interactions between TDP-43 and ataxin-2, and additional findings of an association of ataxin-2 with ALS, the team continued investigating this interaction. Bonini’s lab has long pursued questions about neurodegenerative disease using the fruit fly as an animal model and did so again in this work.

“These model systems are very fast and simpler than mammalian models,” Bonini said. “They allow us to focus on conserved pathways and can be remarkably powerful for giving us insight into pathways involved in disease.”

Using yeast models and the fly, the team showed that genes that modulate cellular structures known as stress granules, which act as holding pens for RNA and proteins when cells are under stress, modify TDP-43 toxicity. Previous work had suggested that ALS patients may have abnormal accumulations of stress granule components, indicating that the structures might somehow be tied to the disease. In flies, the Bonini team found that expression of genes predicted to promote stress granules increased the toxic activity of TDP-43 in genetic screens, underlining the importance of these structures to the pathology of ALS.

Investigating fruit flies engineered to express the human version of TDP-43, they found the flies showed signs of a build-up of stress granule components, as evidenced by an increase in the tagging of a molecule called eIF2-alpha with a phosphate group. eIF2-alpha phosphorylation is associated with formation of stress granules and reduced generation, or translation, of proteins. These flies also had symptoms reflective of ALS; they could not climb as readily as normal flies and had shorter lifespans.

The researchers were able to modulate these symptoms, however, by altering the expression of genes related to eIF2-alpha phosphorylation and stress granules.

From the Editors at Bioscience Technology, December 17, 2013 •

Further, using transgenic flies, the team identified a region of the ataxin-2 protein critical for increasing the detrimental effects of TDP-43. That region is known to be a binding site of a protein called poly-A binding protein, or PABP, that is also known to go to stress granules.

“If you knock out that domain, there is a dramatically reduced interaction between TDP-43 and ataxin-2,” Bonini said. “That, coupled with our other data, is suggestive of the idea that the disease state may be associated with pathological stress granules. Perhaps they are remaining in the cell too long or not being resolved properly.”

As in the flies, PABP may factor into human disease, the researchers found. Examining ALS patients’ spinal cord tissue, they found dense aggregations of PABP in the cytoplasm, reminiscent of stress granules.

Finally, the researchers went back to the fly to see if they could reverse the TDP-43 toxicity.

They fed flies a compound developed by GlaxoSmithKline that inhibits the addition of phosphate groups to eIF2-alpha. Reducing eIF2-alpha phosphorylation is predicted to mitigate stress granule formation and the state of translational repression associated with stress granules. Upon feeding flies, they witnessed a dramatic restoration of physical strength in the flies expressing TDP-43. Those fed the compound retained more climbing ability compared with animals without the compound.

To test the effectiveness of the GSK compound in mammalian cells, the team exposed rat neuron cells expressing TD-43 in culture to the compound, and found it reduced the risk of cell death. The data raise the possibility that the prolonged stress state associated with stress granules and the deleterious effects on cellular pathways associated with such prolonged stress are important in disease.

Bonini suggests the results show promise for a treatment strategy for ALS and highlight again the power that flies, yeast and other seemingly simple model organisms can have in shedding light on human neurological disease.

“We can integrate from a number of extraordinarily powerful systems, including yeast, fly and then mammalian cell culture, to see if, with this united front, we can provide evidence from all spokes that the approach is suggestive of a therapeutic effect,” she said. “They are all important pieces of the puzzle.”

Source: University of Pennsylvania

Biomarkers Help Predict Progress of ALS

Researchers from Penn State Hershey ALS Clinic and Research Center are joined by University of Washington Medical Center for Study

Analysis shows that looking at multiple biomarkers to predict the progression of amyotrophic lateral sclerosis, commonly known as Lou Gehrig’s disease, is not only mathematically possible, it improves upon methods using single biomarkers. (Credit: Christopher "Rice"/Flickr)

Analysis shows that looking at multiple biomarkers to predict the progression of amyotrophic lateral sclerosis, commonly known as Lou Gehrig’s disease, is not only mathematically possible, it improves upon methods using single biomarkers.
(Credit: Christopher “Rice”/Flickr)

By for Penn State

Measuring changes in certain proteins—called biomarkers—in people with amyotrophic lateral sclerosis (ALS) may be a better way to predict progression of the disease. ALS, often referred to as Lou Gehrig’s disease, is a neurological disease in which the brain loses its ability to control movement as motor neurons degenerate. The course of the disease varies, with survival ranging from months to decades.

“The cause of most cases of ALS remains unknown,” says James Connor, distinguished professor of neurosurgery, neural and behavioral sciences and pediatrics at Penn State.

“Although several genetic and environmental factors have been identified, each accounts for only a fraction of the total cases of ALS.” This clinical variation in patients presents challenges in terms of managing the disease and developing new treatments. Finding relevant biomarkers, which are objective measures that reflect changes in biological processes or reactions to treatments, may help address these challenges.

Multiple ALS biomarkers

For the study, researchers studied plasma and cerebrospinal fluid samples previously collected from patients undergoing diagnostic evaluation, who were later identified as having ALS.

Analysis shows that looking at multiple biomarkers to predict progression is not only mathematically possible, it improves upon methods using single biomarkers.

Statistical models analyzing plasma had reasonable ability to predict total disease duration and used seven relevant biomarkers.

For example, higher levels of the protein IL-10 predict a longer disease duration. IL-10 is involved with anti-inflammation, suggesting that lower levels of inflammation are associated with a longer disease duration.

Researchers identified six biomarkers for cerebrospinal fluid. For example, higher levels of G-CSF—a growth factor known to have protective effects on motor neurons, the cells that die in ALS—predicts a longer disease duration.

Perhaps most importantly, the results suggest that a combination of biomarkers from both plasma and cerebrospinal fluid better predict disease duration.

While the size of this study is small, the ability of the specific biomarkers used to predict prognosis suggests that the approach holds promise.

“The results argue for the usefulness of researching this approach for ALS both in terms of predicting disease progression and in terms of determining the impact of therapeutic strategies,” Connor says.

“The results present a compelling starting point for the use of this method in larger studies and provide insights for novel therapeutic targets.”

Xiaowei Su, an graduate student in Connor’s laboratory, led the study in collaboration with Zachary Simmons, director of the Penn State Hershey ALS Clinic and Research Center. Researchers from the University of Washington Medical Center also contributed.

The Paul and Harriett Campbell Fund for ALS Research, the Zimmerman Family Love Fund, and the ALS Foundation, Philadelphia chapter, provided funding for the research.

Source: Penn State

# # #

The Robert A. Stehlin Campaign for ALS (R.A.S.C.A.L.S.) is an all-volunteer 501(c)(3) charity. 100% of all funds raised go to building awareness, treatment research and development, plus ALS family assistance. There are no administrative costs.

Contributions are tax-deductible.

You may also be interested in visiting the RASCALS Store.

The material presented here is for informational purposes only and should not be construed as medical advice, or relied upon as a substitute for medical advice from a health care provider.

ALS Takes a Deep Breath with Diaphragmatic Pacing System

From the Ivanhoe Newswire

COLUMBUS, Ohio (December 19, 2013)  — ALS, also known as Lou Gehrig’s disease, is a progressive neuro-degenerative disease that affects nerve cells in the brain and spinal cord. Sooner or later, it will attack every muscle in a patient’s body, making it impossible to move, even breathe. Now, a new machine is helping people suffering from ALS breathe easier.
Mary Pat Murray has lived with ALS for more than four years. Checkups are not just routine for her, they can be lifesaving.

Traditionally, patients like Mary would use a BiPAP machine to help her breathe. She’d wear a mask, tethered to a ventilator. It would force air into Mary’s lungs.

Now, Mary is the first ALS patient at The Ohio State University to be implanted with a diaphragmatic pacing system to help her strengthen her muscles.

“It feels like a really hard hiccup at first and then eventually you get used to it,” Mary told Ivanhoe.

The external device sends electrical signals to the nerve that controls the diaphragm, replacing signals normally sent by the brain telling it to expand and retract.

“All she needs to do when she is ready at night is to turn that on and it’ll begin to help to contract the diaphragm as she’s breathing,” Stephen J. Kolb, MD, PhD, Co-Director, ALS/MND Clinic, Department of Neurology, The Ohio State University Wexner Medical Center, told Ivanhoe.

The DPS conditions the muscle while Mary sleeps.

“This gives us another tool in our tool belt where we can maybe engage the motor-neurons in the diaphragm; maybe allow the diaphragm to maintain strength longer in ALS, and improve quality of life and lifespan, so it’s very exciting,” Dr. Kolb said.

In just six months, Mary says she’s felt a difference.

“I can carry on a conversation. I can eat. I can drink,” Mary explained.

She is thankful for the technology that allows her to do what most of us take for granted.

Thirty thousand Americans are living with ALS right now. Next year the device will be part of a multi-clinic study to determine if DPS actually helps ALS patients live longer in addition to breathing easier.

# # #

The Robert A. Stehlin Campaign for ALS (R.A.S.C.A.L.S.) is an all-volunteer 501(c)(3) charity. 100% of all funds raised go to building awareness, treatment research and development, plus ALS family assistance. There are no administrative costs.

Contributions are tax-deductible.

You may also be interested in visiting the RASCALS Store.

The material presented here is for informational purposes only and should not be construed as medical advice, or relied upon as a substitute for medical advice from a health care provider.