ALS Research Roundup January 2009

by ALSN Staff on Thu, 2009-01-01 09:16
Article Highlights:

Reasearch Roundup updates as of December 2008:

Stem cells injected into spinal cord slow ALS progression in rats

Nicholas Maragakis
Nicholas Maragakis led a research team that found transplantation into the spinal cord of cells called glial-restricted precursors increased survival time and slowed disease progression in ALS rats.

Scientists at Johns Hopkins School of Medicine in Baltimore and Invitrogen Corp in Carlsbad, Calif., have shown that specialized stem cells known as glial-restricted precursors, or GRPs, can slow disease progression and prolong survival in rats engineered to have a disease that closely mimics human ALS.

The team published its findings online Oct. 19 in Nature Neuroscience. MDA supported the principal investigator, Nicholas Maragakis at Johns Hopkins, for this work.  Jeffrey Rothstein, a longtime MDA grantee and director of MDA’s ALS Center at that institution, was also a collaborator on the project.

The investigators injected the GRPs, a type of immature nervous-system support cell, into the area of the cervical (upper) spinal cord associated with respiratory function, targeting motor neurons (nerve cells that activate muscle) responsible for stimulating the diaphragm. Approximately one-third of the transplanted cells survived through end-stage disease (when the rats were about 170 days old) and, of those, nearly 90 percent differentiated, or matured, into astrocytes, a type of support cell in the nervous system. No damage to the spinal cord, including cyst or tumor formation, was observed.

Rats that received the GRPs lived 16.9 days longer than those that received a placebo. They also showed slower disease progression than the placebo-treated rats did, with longer preservation of respiratory and front-leg function, and motor neuron loss was slowed.

Data from the study indicates the transplanted cells continued to produce a protein that clears the potentially toxic chemical glutamate from the vicinity of nerve cells. Other therapeutic benefits of the GRPs, investigators note, could include a protective effect caused by the release of neurotrophic factors (proteins responsible for the growth and survival of neurons) and reduction of inflammation.

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Third IGF1 trial shows no benefit

In a recently completed third trial of insulin-like growth factor 1 (IGF1) in people with ALS, investigators found the protein did not slow the progression of weakness, prolong survival or change the rate of functional deterioration.

Results were announced Nov. 5 at the 19th International Symposium on ALS/MND in Birmingham, United Kingdom.

A total of 330 participants from 21 centers were randomly selected to receive under-the-skin injections of either IGF1 or a placebo (inert substance) twice daily. Neither the participants nor the investigators knew who received which.

Measurements of muscle testing scores, survival rates and ALS Functional Rating Scale-Revised (ALSFRS-R) revealed no differences between the treatment and placebo groups.

However, this may not mean the end of IGF1-based treatment development. For more on the potential for this substance, see “IGF1: Failure or Success as an ALS Therapy?”

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Surgeon reports on diaphragm pacing in ALS

Diaphragm Pacing System | NeuRx DPS
A diaphragm pacing system, such as this NeuRx DPS, uses electrodes to rhythmically stimulate the diaphragm. Illustration courtesy of Synapse Biomedical

Raymond Onders, director of minimally invasive surgery at University Hospitals Case Medical Center in Cleveland, presented data at the 19th International Symposium on ALS on 88 ALS patients who were involved in trials of an implanted diaphragm pacing system. The symposium was held in Birmingham, United Kingdom, Nov. 3-5. (For more information, see Motor Neurone Disease Association website.)

Onders said diaphragm pacing appears to be well tolerated by people with ALS and to slow respiratory deterioration in this disease. The diaphragm is a major respiratory muscle located under the rib cage.

A diaphragm pacing system uses surgically implanted electrodes in the diaphragm to cause regular, rhythmic muscle contractions. It works similarly to a cardiac pacemaker, which regulates the heartbeat.

The goal of diaphragm pacing, which can be used in combination with noninvasive positive pressure ventilation, is to help maintain respiratory function artificially while preserving as many remaining muscle fibers in the diaphragm as possible.

Onders presented results from a pilot study of 16 patients who received pacing systems and a second, larger study of 72 who got the devices.

In the long-term follow-up of the pilot study, patients with declining respiratory capacity during the lead-in period showed a slower rate of decline after receiving the implanted pacing system, said Onders, who holds the Margaret and Walter Remen Chair in Surgical Innovation at Case. He also said the respiratory items on the ALS Functional Rating Scale did not decline despite deteriorating scores overall.

In summarizing results from all trial participants who received diaphragm pacing systems, Onders noted that some have had the device for as long as two years and that so far no one has been unable to tolerate it. All 26 patients who received a pacing system and also had a gastrostomy (feeding) tube were alive 30 days after pacer insertion, and 83 percent were alive after a year.

Onders said he believes diaphragm pacing systems can be safely implanted and utilized in ALS patients and have a positive effect on diaphragm function.

Hans Katzberg in the Department of Neurology & Neurological Sciences at Stanford (Calif.) University has an MDA grant to study the effect of diaphragm pacing on sleep quality in people with ALS.

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What happens first in ALS could influence treatment development

Damage to muscle fibers may play an earlier and larger role in ALS than previously believed, according to a multinational team of researchers coordinated by MDA grantee Antonio Musaro at the University of Rome (Italy).

The findings of these investigators, published in the Nov. 5 issue of Cell Metabolism, contradict an assumption that ALS researchers have made for decades, which is that the primary targets in the disease process are muscle-controlling nerve cells called motor neurons in the spinal cord and brain.

The new conclusions, if confirmed, would be a positive development for ALS researchers and patients, because muscle tissue is more accessible than the spinal cord or brain and would be easier to reach with therapeutic substances.

Neuromuscular Junction
Nerve and muscle fibers interact at the neuromuscular junction. New research suggests damage to muscle fibers may play an earlier and larger role in ALS than previously realized.

However, in a study partially funded by MDA that was published in Proceedings of the National Academy of Sciences in 2006, Timothy Miller and colleagues showed that partially blocking the effects of an ALS-causing genetic mutation in mice in muscle alone, while leaving the mutation in motor neurons, did not slow the course of the disease.

These investigators interpreted their findings to mean that muscle does not play an important role in ALS, at least in the form caused by mutations in the SOD1 gene, and that the problem is primarily one of motor neuron damage.

But in their new paper, Gabriella Dobrowolny and colleagues (coordinated by Musaro) report having conducted different experiments, and they come to different conclusions about these earlier findings.

In their experiments, the Musaro group found that when mice were genetically engineered to express mutated SOD1 genes and produce a toxic form of the SOD1 protein in skeletal muscles alone, they developed severe muscle wasting without any loss of motor neurons.

The muscle fibers with the mutated SOD1 genes sustained damage to their protective membranes, showed a change in metabolic activity, and didn’t function normally, the investigators say.

“The results of this study challenge the accepted dogma that motor neuron degeneration ... is the primary cause of muscle atrophy [wasting],” they note.

They say their findings don’t necessarily contradict the report from Miller and co-workers. Instead, they speculate, the reason that group didn’t see any slowing of the ALS disease process after blocking mutated SOD1 in muscle tissue is that the SOD1 wasn’t blocked completely and therefore continued to exert its toxic effect on muscle fibers.

They further speculate that toxic signals originating from skeletal muscle fibers may compromise the nerve-to-muscle connections. Damage to these connections, known as neuromuscular junctions, could, in this new way of looking at ALS, contribute to the loss of motor neurons.

“Taken together,” Musaro said, “these results support the redefinition of ALS as a multisystem disease in which in structural, physiological and metabolic alterations in different cell types — muscle cells, motor neurons and motor-neuron support cells — may act synergistically to exacerbate the disease.” He added that, from a therapeutic point of view, “perhaps the most powerful future approach would be to target both spinal cord and muscle.”

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VEGF-B saves nerve cells, lengthens life in ALS rats

A protein called VEGF-B (vascular endothelial growth factor B) protects nerve cells that control muscle action and prolongs the lives of ALS rats, an MDA-supported research team has found.

MDA grantee Peter Carmeliet at the Flanders Institute for Biotechnology at the University of Leuven (Belgium) coordinated the team, which announced its findings in the Oct. 15 issue of the Journal of Neuroscience.

Earlier work by Carmeliet and colleagues has shown that a structurally similar protein, VEGF (vascular endothelial growth factor, which encourages the growth of blood vessels), also has the ability to protect these nerve cells, called motor neurons. However, concerns about the potential for this protein to cause excessive proliferation of blood vessels has limited its development as a neuroprotective agent.

This spring, Xuri Li at the National Institutes of Health, and colleagues, found that VEGF-B, which comes from a gene different from the VEGF gene, also has potent cell-protecting properties in the nervous system. Despite its similar name, they found, it doesn’t cause growth of new blood vessels. Li’s group found VEGF-B minimized damage to the optic nerve, retina and brain in mice with injuries to these areas.

Now, Carmeliet and colleagues have found an infusion of VEGF-B into the spinal fluid of ALS rats protected nerve cells and prolonged life by an average of 15 days compared to survival for untreated ALS rats, a difference considered significant. VEGF-B treatment appears safer than treatment with VEGF, since it didn’t cause blood-vessel growth or leakiness in brain membranes, which are concerns with VEGF.

ALS rats treated with VEGF-B also maintained the ability to stay on a rotating rod 11 days longer than the untreated rats did, but this difference was not considered statistically significant.

“Overall, delivery of VEGF-B may offer therapeutic opportunities for neurodegenerative diseases that develop spontaneously,” the researchers say.

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ALS Clinical Research Network project selection under way

Physical Therapy
Five MDA/ALS Centers will participate in the new ALS Clinical Research Network. A study of blood lipid levels in ALS is among the proposed projects.

Investigators from the five centers that comprise the ALS-focused aspect of MDA’s new Clinical Research Network have begun selecting and prioritizing projects. (See “ALS to be a major focus,” Research Roundup, October 2008.)

Among them is a study of hyperlipidemia (raised levels of fatty molecules, or “lipids,” in the blood) as a predictor of disease progression.

Results from a French study, published in March 2008 in the journal Neurology, suggested that elevated levels of lipids in the blood, known to be risk factors for cardiovascular disease, actually may be a good thing in ALS. (See “Does a high serum cholesterol level increase survival time in ALS?”, Research Roundup, May 2008.)

Also spurring interest in hyperlipidemia and ALS is a possible connection between the use of cholesterol-lowering “statin” medications such as atorvastatin (Lipitor), lovastatin (Mevacor), simvastatin (Zocor) and others, and an elevated risk of developing ALS. This possible association was the focus of a 2007 report from the World Health Organization.

On the other hand, studies have shown evidence of inflammation in the spinal cords of ALS patients, and statins are known to have anti-inflammatory properties. At the Methodist Neurological Institute in Houston, atorvastatin is being investigated in a clinical trial for its potential to positively affect the course of ALS.

Other ALS projects identified by the investigators as priorities include the development of meaningful measures for use in clinical trials, and development of a system to select, design and perform studies on treatments in phase 2 clinical trials.

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Teva to test blocker of AMPA receptors in large-scale trial

Teva Pharmaceutical Industries, a global pharmaceutical company based in Petach Tikva, Israel, is conducting a multicenter, one-year study of an experimental oral drug called talampanel, in which two doses of the drug will be compared to a placebo in people with ALS.

Teva is seeking approximately 100 participants for study at seven U.S. sites and some 400 additional participants from other countries.

Talampanel blocks AMPA receptors, molecular docking sites for glutamate, a potentially toxic nervous-system chemical. In an earlier, small study, there were indications that people who took talampanel did better on the ALS Functional Rating Scale than those who took a placebo.

This new, larger study will assess safety and effectiveness of talampanel in ALS and is open to adults who have ALS symptoms that began no more than three years before their screening visit; who are not using any assisted ventilation; don’t have a gastrostomy tube; and meet other criteria. Contact Mary Lou Watson at SUNY Upstate Medical University in Syracuse, N.Y., at (315) 464-5004.

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