2 More ALS R&D “Breakthroughs” in March 2014 … hope it doesn’t take another 7-10 years to introduce these to HUMANS
I don’t think I have that long …
Experimental stroke drug also shows promise for people with Lou Gehrig’s disease
Date: March 3, 2014
Source: University of Southern California - Health Sciences
Neuroscientists have found that early muscle impairment related to Lou Gehrig’s disease, also called amyotrophic lateral sclerosis, or ALS, in mice is proportional to the degree of damage to the blood-spinal cord barrier, which protects the central nervous system from toxins. Repairing damage to and restoring the blood-spinal cord barrier’s integrity with an experimental neurovascular medicine being studied in human stroke patients appears to delay disease progression.
Credit: Photo courtesy of Ethan A. Winkler and Berislav V. Zlokovic/University of Southern California
[Click to enlarge image]
A fluorescent image shows cells of the neurovascular unit in the mouse spinal cord, which consists of motor neurons (green) and blood vessels containing pericytes (red) and endothelial cells (blue). Winkler et al. show that disruption of blood vessels accelerates injury of motor neurons in amyotrophic lateral sclerosis.
Keck School of Medicine of USC neuroscientists have unlocked a piece of the puzzle in the fight against Lou Gehrig’s disease, a debilitating neurological disorder that robs people of their motor skills. Their findings appear in the March 3, 2014, online edition of the Proceedings of the National Academy of Sciences of the United States of America, the official scientific journal of the U.S. National Academy of Sciences.
"We know that both people and transgenic rodents afflicted with this disease develop spontaneous breakdown of the blood-spinal cord barrier, but how these microscopic lesions affect the development of the disease has been unclear," said Berislav V. Zlokovic, M.D., Ph.D., the study’s principal investigator and director of the Zilkha Neurogenetic Institute at USC. "In this study, we show that early motor neuron dysfunction related to the disease in mice is proportional to the degree of damage to the blood-spinal cord barrier and that restoring the integrity of the barrier delays motor neuron degeneration. We are hopeful that we can apply these findings to the corresponding disease mechanism in people. "
In this study, Zlokovic and colleagues found that an experimental drug now being studied in human stroke patients appears to protect the blood-spinal cord barrier’s integrity in mice and delay motor neuron impairment and degeneration. The drug, an activated protein C analog called 3K3A-APC, was developed by Zlokovic’s start-up biotechnology company, ZZ Biotech.
Lou Gehrig’s disease, also called amyotrophic lateral sclerosis, or ALS, attacks motor neurons, which are cells that control the muscles. The progressive degeneration of the motor neurons in ALS eventually leads to paralysis and difficulty breathing, eating and swallowing.
According to The ALS Association, approximately 15 people in the United States are diagnosed with ALS every day. It is estimated that as many as 30,000 Americans live with the disease. Most people who develop ALS are between the ages of 40 and 70, with an average age of 55 upon diagnosis. Life expectancy of an ALS patient averages about two to five years from the onset of symptoms.
ALS’s causes are not completely understood, and no cure has yet been found. Only one Food and Drug Administration-approved drug called riluzole has been shown to prolong life by two to three months. There are, however, devices and therapies that can manage the symptoms of the disease to help people maintain as much independence as possible and prolong survival.
The above story is based on materials provided by University of Southern California - Health Sciences. Note: Materials may be edited for content and length.
- E. A. Winkler, J. D. Sengillo, A. P. Sagare, Z. Zhao, Q. Ma, E. Zuniga, Y. Wang, Z. Zhong, J. S. Sullivan, J. H. Griffin, D. W. Cleveland, B. V. Zlokovic. Blood-spinal cord barrier disruption contributes to early motor-neuron degeneration in ALS-model mice. Proceedings of the National Academy of Sciences, 2014; DOI:10.1073/pnas.1401595111
- II. Key player in motor neuron death in Lou Gehrig’s disease identified
Key player in motor neuron death in Lou Gehrig’s disease identified
Date: March 26, 2014
Source: Nationwide Children’s Hospital
Amyotrophic lateral sclerosis, also known as Lou Gehrig’s disease, is marked by a cascade of cellular and inflammatory events that weakens and kills vital motor neurons in the brain and spinal cord. The process is complex, involving cells that ordinarily protect the neurons from harm. Now, a new study points to a potential culprit in this good-cell-gone-bad scenario, a key step toward the ultimate goal of developing a treatment.
Amyotrophic lateral sclerosis, also known as Lou Gehrig’s disease, is marked by a cascade of cellular and inflammatory events that weakens and kills vital motor neurons in the brain and spinal cord. The process is complex, involving cells that ordinarily protect the neurons from harm. Now, a new study by scientists in The Research Institute at Nationwide Children’s Hospital points to a potential culprit in this good-cell-gone-bad scenario, a key step toward the ultimate goal of developing a treatment.
Motor neurons, or nerve cells, in the brain and spinal cord control the function of muscles throughout the body. In amyotrophic lateral sclerosis (ALS), motor neurons die and muscles weaken. Patients gradually lose the ability to move and as the disease progresses, are unable to breathe on their own. Most people with ALS die from respiratory failure within 3 to 5 years from the onset of symptoms.
For the study, published online this month in Neuron, researchers examined a protein involved in transcriptional regulation, called nuclear factor-kappa B (NF-κB), known to play a role in the neuroinflammatory response common in ALS. NF-ƘB has also been linked to cancer and a number of other inflammatory and autoimmune diseases.
Using animal models, the researchers studied disease progression in mice in which NF-ƘB had been inhibited in two different cell types — astrocytes, the most abundant cell type in the human brain and supporters of neuronal function; and microglia, macrophages in the brain and spinal cord that act as the first and main form of defense against invading pathogens in the central nervous system. Inhibiting NF-ƘB in microglia in mice slowed disease progression by 47 percent, says Brian Kaspar, MD, a principal investigator in the Center for Gene Therapy at Nationwide Children’s and senior author of the new study.
"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," Dr. Kaspar says. "And our findings suggest that the microglia utilize an NF-κB-mediated inflammatory response as one of its weapons."
Inhibiting the protein in astrocytes had no impact on disease progression, so the search for the weapons that cell type uses against motor neurons continues. These preliminary findings also don’t tell scientists how or why NF-κB turns the ordinarily protective microglia into neuron-killing molecules. But despite the mysteries that remain, the study moves scientists closer to finding a treatment for ALS.
The search for an ALS therapy has been focused in two directions: identifying the trigger that leads to disease onset and understanding the process that leads to disease progression. Changes in motor neurons are involved in disease onset, but disease progression seems to be dictated by changes to astrocytes, microglia and oligodendrocytes. Some cases of ALS are hereditary but the vast majority of patients have no family ties to the disease. The complexity of the disease and the lack of a clear familiar tie make screening before disease onset nearly impossible, highlighting the importance of slowing the disease, Dr. Kaspar says.
"Focusing on stopping the changes that occur in astrocytes and microglia has clinical relevance because most people don’t know they’re getting ALS, says Dr. Kaspar, who also is an associate professor of pediatrics and neurosciences at The Ohio State University College of Medicine. "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 above story is based on materials provided by Nationwide Children’s Hospital.Note: Materials may be edited for content and length.
- Ashley E. Frakes, Laura Ferraiuolo, Amanda M. Haidet-Phillips, Leah Schmelzer, Lyndsey Braun, Carlos J. Miranda, Katherine J. Ladner, Adam K. Bevan, Kevin D. Foust, Jonathan P. Godbout, Phillip G. Popovich, Denis C. Guttridge, Brian K. Kaspar. Microglia Induce Motor Neuron Death via the Classical NF-κB Pathway in Amyotrophic Lateral Sclerosis. Neuron, 2014; 81 (5): 1009 DOI:10.1016/j.neuron.2014.01.013