CIRM-Funded Clinical Trial for ALS Given Go Ahead to Treat Patients

October 24, 2016 Oakland, CA – An ingenious method that uses a patient as their own control has been given clearance to start a clinical trial to treat amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s Disease. The California Institute for Regenerative Medicine (CIRM) is funding the trial. ALS is a devastating disease that destroys nerve cells in the brain or spinal cord. There is no treatment or cure, and the average life expectancy for someone with ALS is 3 - 4 years.  Every 90 minutes someone in the US is diagnosed with ALS. Every 90 minutes someone in the US dies of ALS. The clinical trial is led by Clive Svendsen, PhD, director of the Board of Governors Regenerative Medicine Institute at Cedars-Sinai, who has spent a dozen years developing the new approach: “Any time you’re trying to treat an incurable disease, it is a long shot, but we believe the rationale behind our new approach is strong.” The new approach targets motor neurons, cells which help control movement in the body and that are killed by ALS. Svendsen and his team are using specially engineered stem cells to deliver a protein – GDNF – that is essential to the health of motor neurons. The hope is that by providing the motor neurons with GDNF they can keep them alive. How they intend to prove that is the ingenious part. Previous studies have shown that patients with ALS experience the same rate of deterioration of movement in both legs simultaneously. Using a new device developed specifically for this trial, Svendsen intends to inject the GDNF-producing stem cells in one side of the spinal cord, into an area that controls movement in just one [...]

ALS Ice Bucket Challenge Funding Leads to New Genetic Findings

ABC News - July 27, 2016 The ALS Ice Bucket Challenge, which went viral in 2014 as a fundraiser for research, has resulted in far more than just funny YouTube videos of people dumping icy water on themselves for a good cause. Researchers credit the $220 million raised as key in funding a new study that has possibly identified a common gene that contributes to amyotrophic lateral sclerosis (ALS). ALS is a neurodegenerative disease that affects nerve cells in the spinal cord leading to loss of control over muscles. Eventually, the disease leads to total paralysis and death. In a study published in The Nature Genetics Journal, researchers from various institutions, including the University of Massachusetts Medical School and the University Medical Center Utrecht, identified the gene NEK1 as a common gene that could have an impact on who develops the disease. Variants of the gene appear to lead to increased risk of developing ALS, according to preliminary findings. Researchers said they're eager to understand more about the disease. Researchers in 11 countries studied 1,000 families in which a family member developed ALS and conducted a genome-wide search for any signs that a gene could be leading to increased ALS risk. After identifying the NEK1 gene, they also analyzed 13,000 individuals who had developed ALS despite no family history and found they had variants in that same gene, again linking that gene with increased ALS risk. “The discovery of NEK1 highlights the value of ‘big data’ in ALS research," Lucie Bruijn, the chief scientist for the ALS Association, said in a statement. "The sophisticated gene analysis that led to this finding was only possible because of the large number of ALS samples available." Multiple initiatives [...]

From labs to lives: Self-replicating cells help treat neuro disorders

July 27, 2016 Scientists estimate that human bodies contain anywhere from 75 to 100 trillion cells. And of these cells, there are hundreds of different types. Yet, one cell type in particular has captured the fascination of assistant professor David Brafman: the human pluripotent stem cell (hPSC).Assistant professor David Brafman mentoring biomedical engineering junior Lexi Bounds, who plans to pursue a career in stem cell research. Photographer: Jessica Hochreiter/ASU As self-replicating cells — capable of dividing and forming new cells — hPSCs offer immense research potential. They are able to provide the raw material needed to generate the hundreds of different cell types that comprise the human body. Think of it as a reverse e pluribus unum. Something like out of one, come many. Brafman has received a $420,000 grant from the National Institutes of Health to take discoveries related to hPSCs out of the research lab and into the clinical setting where they can transform, even save, lives. In particular, his research focuses on using the remarkable qualities of hPSCs to generate large quantities of hPSC-derived neurons, which are instrumental in advances toward the study and treatment of Alzheimer’s disease, ALS, spinal cord injuries and other neurodegenerative disorders. “Neurodegenerative diseases and disorders remain some of the leading causes of mortality and morbidity in the United States,” said Brafman, a biomedical engineering faculty member in ASU’s Ira A. Fulton Schools of Engineering. According to the Alzheimer’s Association, the disease affects more than 130,000 individuals statewide and is the fifth leading cause of death in Arizona. “Several bottlenecks limit the translation of hPSCs and their derivatives from bench to bedside,” said Brafman, referring to the need to take this research from the laboratory bench to the clinical [...]

More Good News for Stem Cell Transplants in ALS

Pauline Anderson July 05, 2016 Medscape Transplantation of human spinal cord-derived neural stem cells (HSSCs) in patients with amyotrophic lateral sclerosis (ALS) is safe and does not accelerate progression of the disease, according to results of a new phase 2 study. A phase 1 single-center study of 15 patients, carried out at Emory University in Atlanta, Georgia, found that transplanting a single concentration of HSSCs per injection is safe. This new phase 2, dose-escalation study, which included 15 additional participants at 3 sites, involved an increased concentration of cells and more injection sites. "Here, we have shown that, with a few exceptions, patients with ALS can tolerate up to 20 injections with 400,000 cells per injection into the lumbar and cervical spinal cord, including 2 successive procedures totaling 40 injections and 16 million cells," write the authors, led by Jonathan D. Glass, MD, Department of Neurology, Emory University School of Medicine. "Thus, we conclude that the injection procedure, as well as the introduction of high doses of HSSCs into the spinal cord, is relatively safe." The study was published online June 29 in Neurology. No Disease-Modifying Treatment ALS is a neurodegenerative disease caused by systematic unravelling of the motor network, resulting in progressive loss of upper and lower motor neurons. It leads to muscle wasting and weakness and ultimately to ventilator failure and death. There are currently no treatments to prevent this progression. Stem cells are being studied as a potential therapy because these cells can differentiate into multiple cell types, possibly repairing or replacing injured cells. For this new study, patients with ALS had to be within 24 months of symptom onset at the time of screening and able to undergo transplant surgery no more than 36 [...]

Jammed Up Cellular Highways May Initiate Dementia and ALS

Molecular therapy partially relieves havoc wreaked by gene mutation in human and fly cells August 26, 2015 FAST FACTS: The C9orf72 mutation is the most common known genetic risk factor for 40 percent of inherited cases of amyotrophic lateral sclerosis (ALS) and a similar percentage of inherited cases of frontotemporal dementia. Researchers say they have discovered how the mutation causes long strands of RNA to block the pathways that normally move proteins into a cell’s nucleus. In diseased brain cells affected by the mutation, proteins clump up on the nuclear membrane, causing molecular traffic jams. The research team successfully used a molecular therapy to reopen the blocked pathways in human and fly cells. Neurons, red, created from ALS patients bearing the C9orf72 mutation, show clumps of the RanGAP protein, yellow, in their nuclei, white. The nuclei of other cells are in blue. Credit: Jeffrey Rothstein laboratory, Johns Hopkins Medicine Johns Hopkins researchers say they have discovered some of the first steps in how a very common gene mutation causes the brain damage associated with both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). They report that the altered C9orf72 gene, located on human chromosome 9, causes RNA molecules to block critical pathways for protein transport, causing a molecular traffic jam outside brain cell nuclei and affecting their operations and survival. In a proof-of-concept experiment, the researchers also say that a molecular therapy eased the jam and restored molecular flow into the cell’s core. A report on the work will be published online on Aug. 26 in the journalNature. “The discovery several years ago of this mutation — the most common one linked to ALS and FTD — was really a game changer for the field [...]

Researchers home in on biological cause of ALS

A mutation linked to amyotrophic lateral sclerosis interferes with the transport of proteins in and out of a cell’s nucleus. Targeting this pathway with drugs or therapies may one day help patients with neurodegenerative disease. AUG 262015 Aaron Gitler A defect in how proteins are transported inside cells may be at least partially responsible for some symptoms of amyotrophic lateral sclerosis, according to a study by researchers at the Stanford University School of Medicine. The researchers found that cells with a mutation associated with the disease were hampered in their ability to move proteins into and out of the nucleus, a cell’s command center. The findings are among the first to open a window into the molecular causes of the deadly condition. Also known as Lou Gehrig’s disease, ALS is a progressive neuromuscular disorder. Although it’s unknown what causes many cases of the disease, a genetic stutter in a region of DNA called C9orf72 has been associated with the development of both ALS and another related neurodegenerative disorder called frontotemporal dementia. In this region, the DNA sequence is made up of a six-nucleotide pattern, which repeats abnormally in some people with ALS or FTD. “Healthy people have two to five repeats of this six-nucleotide pattern,” said Aaron Gitler, PhD, associate professor of genetics. “But in some people, this region is expanded into hundreds or thousands of copies. This mutation is found in about 40 to 60 percent of ALS inherited within families and in about 10 percent of all ALS cases. This is by far the most common cause of ALS, so everyone has been trying to figure out how this expansion of the repeat contributes to the disease.” Although the repeat occurs in a region [...]

Biogen, ALS Association, and Columbia University Med Center to Explore ALS Genetics

Source: © iceteastock/Fotolia.com Aug. 18, 2015 - Biogen, the ALS Association, and Columbia UniversityMedical Center (CUMC) agreed to collaborate to better understand the differences and commonalities in the ALS disease process and how genes influence the clinical features of the disease. The project, “Genomic Translation for ALS Clinical care” (GTAC), will involve a combination of next-generation sequencing and detailed clinical phenotyping in 1,500 people with ALS. The goal of the project is to provide a basis for the development of precision medicine, or more individually tailored therapies for ALS. “We want to bring genomics right to the point of care in ALS where instead of focusing on retrospective DNA samples with limited clinical information, we focus on patients who are under active clinical management,” said Lucie Bruijn, Ph.D., chief scientist at the ALS Association. “By focusing on patients seen by participating ALS clinics, this project will allow investigators to ask how different genetic causes of ALS translate into different clinical consequences.” An explicit aim of the collaboration is to set the stage for a nationwide effort to ensure the genomic characterization of all patients with ALS. “We know that ALS is not just one disease,” explained Tim Harris, svp, precision medicine at Biogen. “This study will help in developing a detailed understanding of how different genes contribute to different clinical forms of ALS. This will in turn help us design better, more focused clinical trials for the development of more effective treatments. This kind of ‘precision medicine,’ in which a treatment is tailored to a person’s unique genetic make-up, is already being used in the cancer field. It is an approach we feel is ready for ALS too.” “Until recently, most large-scale genomics studies used archived [...]

Neurons’ broken machinery piles up in ALS

Wednesday, August 12, 2015, 11 a.m. EDT NIH scientists identify a transport defect in a model of familial ALS A healthy motor neuron needs to transport its damaged components from the nerve-muscle connection all the way back to the cell body in the spinal cord. If it cannot, the defective components pile up and the cell becomes sick and dies. Researchers at the National Institutes of Health’s National Institute of Neurological Disorders and Stroke (NINDS) have learned how a mutation in the gene for superoxide dismutase 1 (SOD1), which causes ALS, leads cells to accumulate damaged materials. The study, published in the journal Neuron, suggests a potential target for treating this familial form of ALS. Cellular garbage causes neurons to break down. A genetic mutation linked to ALS prevents motor neurons (pictured above) from getting rid of defective parts. Courtesy of Sheng Lab, NINDS More than 12,000 Americans have ALS, also known as Lou Gehrig’s disease, and roughly 5-10 percent of them inherited a genetic mutation from a parent. These cases of familial ALS are often caused by mutations in the gene that codes for SOD1, an important enzyme located in the neuron’s mitochondria, the cell’s energy-producing structures. This mutation causes the death of motor neurons that control the patient’s muscles, resulting in progressive paralysis. “About 90 percent of the energy in the brain is generated by mitochondria,” said Zu-Hang Sheng, Ph.D., an NINDS scientist and the study’s senior author. “If the mitochondria aren’t healthy, they produce energy less efficiently; they can also release harmful chemicals called reactive oxygen species that cause cell death. As a consequence, mitochondrial damage can cause neurodegeneration.” In healthy neurons, storage containers called late endosomes collect damaged mitochondria and various [...]

Research Sheds Light on How Neurons Control Muscle Movement

New research involving people diagnosed with Lou Gehrig’s disease sheds light on how individual neurons control muscle movement in humans — and could help in the development of better brain-controlled prosthetic devices. JUN 232015 Studying the brain activity of two patients with Lou Gehrig's disease has given researchers insight into how neurons control muscle movement. Oliver Burston                               Stanford University researchers studying how the brain controls movement in people with paralysis, related to their diagnosis of Lou Gehrig’s disease, have found that groups of neurons work together, firing in complex rhythms to signal muscles about when and where to move. “We hope to apply these findings to create prosthetic devices, such as robotic arms, that better understand and respond to a person’s thoughts,” said Jaimie Henderson, MD, professor of neurosurgery. A paper describing the study was published online June 23 in eLife. Henderson, who holds the John and Jene Blume-Robert and Ruth Halperin Professorship, and Krishna Shenoy, PhD, professor of electrical engineering and a Howard Hughes Medical Institute investigator, share senior authorship of the paper. The lead author is postdoctoral scholar Chethan Pandarinath, PhD. The study builds on groundbreaking Stanford animal research that fundamentally has changed how scientists think about how motor cortical neurons work to control movements. “The earlier research with animals showed that many of the firing patterns that seem so confusing when we look at individual neurons become clear when we look at large groups of neurons together as a dynamical system,” Pandarinath said. Previously, researchers had two theories about how neurons in the motor cortex might control movement: One was that these neurons fired in patterns that [...]

A New Grasp on Robotic Glove

Mon, 06/08/2015 - 10:15am- Harvard University The soft robotic glove could help patients suffering from muscular dystrophy, amyotrophic lateral sclerosis, incomplete spinal cord injury, or other hand impairments regain some independence and control of their environment. (Photo: Courtesy of Wyss Institute at Harvard University)Having achieved promising results in proof-of-concept prototyping and experimental testing, a soft robotic glove under development by Conor Walsh and a team of engineers at the Harvard John A. Paulson School of Engineering and Applied Sciences (SEAS) and Wyss Institute for Biologically Inspired Engineering could someday help people suffering from loss of hand motor control regain some of their independence. Most patients with partial or total loss of their hand motor abilities due to muscular dystrophy, amyotrophic lateral sclerosis (ALS), or incomplete spinal cord injury report a greatly reduced quality of life because of their inability to perform many activities of daily living. Tasks often taken for granted by the able-bodied — buttoning a shirt, picking up a telephone, using cooking and eating utensils — become frustrating, nearly impossible feats due to reduced gripping strength and motor control. The stage is now set for that to change, however, thanks to Walsh’s expertise in soft, wearable robotic systems and a development approach that involves the glove’s potential end users in every step of testing and development. The holistic approach ensures that technology development goes beyond simple functionality to incorporate social and psychological elements of design that promote seamless adoption by its end users. “From the start of this project, we’ve focused on understanding the real-world challenges facing these patients by visiting them in their homes to perform research,” said Walsh, an assistant professor of mechanical and biomedical engineering and founder of the Harvard Biodesign [...]