Research news as of December 2010:
FDA approves emotional-expression medication
|Nuedexta is now approved to treat unwanted episodes of laughing or crying (PBA) that sometimes occur in association with ALS.
Avanir Pharmaceuticals announced Oct. 29, 2010, that the U.S. Food and Drug Administration approved its drug Nuedexta for the control of pseudobulbar affect (PBA) in ALS. (Earlier versions of Nuedexta were known as Neurodex, Zenvia and AVP923.)
PBA is a neurological disorder in which episodes of laughing or crying occur out of proportion or unrelated to mood. It’s frequently seen in people with ALS, and can cause much distress and embarrassment. Neudexta also was approved for use in PBA occurring in multiple sclerosis (a disorder not in MDA’s program).
A phase 3 trial of Nuedexta included approximately 300 people with PBA secondary to ALS or multiple sclerosis. The investigators found that (compared to a placebo) the drug reduced the number of episodes of unwanted laughing or crying, and that it was generally safe and well-tolerated for 12 weeks.
Each Nuedexta capsule contains 20 milligrams of dextromethorphan and 10 milligrams of quinidine. Full information about Nuedexta can be found at the Avanir website.
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NG2+ cells may provide clues to disease process
Researchers supported in part by MDA have identified abnormalities in “NG2+” nervous system cells in ALS-affected mice that appear to play a role in the ALS disease process.
The research team, which published its findings in the Nov. 18, 2010, issue of the journal Neuron, found that NG2+ cells (which normally mature into nervous system support cells called oligodendrocytes) exhibit significant developmental differences in healthy mice compared to mice with a disease resembling ALS. MDA supported Jeffrey Rothstein at Johns Hopkins University in Baltimore for this work.
In the spinal cords of ALS mice, the NG2+ cells grew and multiplied at a far greater speed than they did in normal mice, after which they developed into abnormal oligodendrocytes and then quickly died — prompting investigators to speculate that these cells may be involved in the ALS disease process.
Further examination of the differences between NG2+ cells in normal mice and mice with ALS could provide investigators with valuable information about the molecular underpinnings of ALS and possible therapy design.
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MDA allots $2.3 million to ALS research
MDA has approved funding totaling nearly $2.3 million for research targeted at stopping ALS.
MDA’s Board of Directors met Dec. 10, in New York City, where it reviewed and approved the new grants based on recommendations from the MDA Scientific and Medical Advisory Committees. Applications were scored and recommended for approval based on the capabilities of the applicant, the scientific merit of the project, and the proposal’s relevance to understanding and developing treatments for the disease.
The new grants support projects covering a variety of crucial areas of investigation in ALS-related research. These include elucidation of the molecular mechanisms of the disease in worm (nematode) and animal models; the cause of protein misfolding in the disease; regulation of motor neuron differentiation (maturation); and creation of a research model of the disease developed with ALS-affected human induced pluripotent stem (iPS) cells.
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Stem cell trial moves forward
|Participants in the Neuralstem stem cell trial will undergo an initial MRI of the brain and spinal cord and subsequent MRIs of the lower cord, as well as many other tests.
The biotherapeutics company Neuralstem is moving its clinical trial of neural stem cells in people with ALS into its next stage, following a thumbs-up from the trial’s safety monitoring board, the company announced Oct. 18, 2010.
This phase 1 trial, designed mainly to assess the safety and feasibility of injecting neural stem cells into the spinal cords of people with ALS, is being conducted at Emory University in Atlanta, under the supervision of neurologists Eva Feldman and Jonathan Glass. Glass directs the MDA/ALS Center at Emory, but MDA is not funding this trial.
The cells are derived from the spinal cord of a human fetus. In Neuralstem’s laboratories, the cells have been made to multiply and create a supply for patients in research studies. Both the cells and the procedure for injecting them are experimental. Benefit to participants is not expected from this trial, although a great deal about the injection procedure and the fate of the injected cells is likely to be learned.
The first stage of the trial involved injecting the cells into the spinal cords of six people with ALS who had lost the ability to walk before entering the study. Subsequent stages involve injecting cells into small numbers of people who are at earlier stages of the disease.
For details about the study, see the Emory ALS Center website and select Stem Cell Trial.
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VEGF activator shows safety, hints of efficacy
|SB509 injections have had a positive effect on ankle and toe muscle strength, as well as disease progression.
Continued safety and hints of efficacy were demonstrated for a phase 2 trial of SB509, an experimental ALS treatment being developed by Sangamo BioSciences. The company reported the trial results at the annual meeting of the Society for Neuroscience in San Diego in November 2010.
SB509 is designed to increase production of a protein called vascular endothelial growth factor A (VEGF A). Its development is based on the hypothesis that increasing the amount of VEGF A could be helpful in ALS, because genetic mutations that reduce VEGF A levels have been linked to ALS progression, and levels of this protein are lower than normal in the spinal fluid of ALS patients.
On Nov. 17, 2010, Sangamo presented results of a phase 2 trial of SB509 in 45 people with ALS who received injections of the drug twice, at day 0 and day 90 of the study. Thirty-nine participants received injections into leg, arm and neck muscles, and six received injections only into the leg muscles, and all were assessed on day 120 via a variety of measures.
On day 120, the investigators saw a trend toward delayed deterioration of ankle and toe muscle strength in 40 percent (18) of the SB509-treated trial participants. Some participants showed encouraging signs on electrophysiologic testing, and some showed a trend toward slowing of disease progression.
In a Nov. 17 press release, Sangamo’s chief medical officer Dale Ando called the results “very encouraging,” given the limited amount of the experimental drug the trial participants received. He said future trials would likely include “more frequent and focused dosing with SB509.”
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MDA Network studying ‘meaningful’ changes in ALS
|The changes in function that ALS-affected families consider "meaningful" may differ from those that show up in statistical analyses of trial results.
The MDA/ALS Clinical Research Network is supporting and recruiting participants for a five-center study to develop a scale of “clinically meaningful” changes in ALS. The investigators want to find out the size of a change in medical, psychosocial, or quality-of-life status that people with ALS and their caregivers consider meaningful. Changes that patients and caregivers consider meaningful may or may not correspond to statistical differences detected in clinical trials, the investigators say, and it’s important for regulatory agencies and those developing ALS treatments to understand patients’ and caregivers’ perspectives.
There are five locations for this MDA-supported study, all of which are sites of MDA/ALS centers: Columbia University in New York; Massachusetts General Hospital in Boston; Methodist Neurological Institute in Houston; California Pacific Medical Center in San Francisco; and Emory University in Atlanta.
The investigators are seeking 100 patient-caregiver pairs to answer questionnaires, either in person or over the phone, four times during a six-month period. Participants with ALS must be 20-85 years old, have a family caregiver willing to participate, live near a study site and meet other study criteria.
Contact Allison DiRienzo at the main coordinating center, Columbia University, at (212) 305-4746 or firstname.lastname@example.org for more information.
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Immune system regulator shows safety in ALS
Neuraltus Pharmaceuticals announced Nov. 30, 2010, that its experimental drug NP001 was safe and well-tolerated at four different dose levels when given as a single intravenous treatment to people with ALS. There also was a statistically significant improvement in blood levels of a biological marker thought to be involved in the ALS disease progression. NP001 is a small molecule designed to regulate the activation of immune system cells called macrophages.
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Misfolded SOD1 found in sporadic ALS spinal cords
A new study suggests misfolding of the SOD1 protein may be a common contributor not only to familial ALS caused by mutations in the SOD1 gene but to the more common sporadic (noninherited) form of the disease as well.
If confirmed, the findings could mean that many familial and sporadic forms of ALS share a common factor — protein misfolding. The findings also could mean that therapies being developed to combat mutated SOD1 protein could have application beyond familial SOD1-related ALS.
|Proteins have to fold into precise shapes. Misfolded SOD1 protein molecules can impair transport along nerve fibers, new findings show.
Robert Brown and Daryl Bosco, neurobiologists and ALS investigators at the University of Massachusetts Medical School in Worcester, coordinated the research team, which published its findings online Oct. 17, 2010, in Nature Neuroscience.
The team found that SOD1 protein molecules made from a normal (nonmutated) SOD1 gene can assume an abnormal and toxic shape after undergoing a chemical change called oxidation. Once oxidized, they can behave much like SOD1 protein molecules made from mutated SOD1 genes, a known cause of familial ALS.
Misfolded SOD1 protein molecules were detected in the spinal cords of four out of nine people who had died of sporadic ALS, and were not seen in 17 people who had died of causes not related to ALS.
“We’re now working to determine the nature of the SOD1 modification in patients,” Bosco said. “It may be oxidation and/or other perturbations to the SOD1 protein.”
The scientists performed experiments showing that misfolded SOD1 resulting from either mutated SOD1 genes or SOD1 proteins oxidized in the laboratory can impair the transport of substances along nerve fibers, a problem believed to contribute to the ALS disease process.
Protein misfolding in ALS is an area of active research (see Why Does ALS Spread?).
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21st symposium on ALS/MND held in December
The 21st International Symposium on ALS/Motor Neuron Disease, organized by the Motor Neurone Disease Association, a British group, was held Dec. 11-13, 2010, in Orlando, Fla.
Two parallel meetings were held, one on biomedical research, and the other on advances in the care and clinical management of people with ALS. Several of the presentations were delivered by MDA-supported researchers and MDA-associated clinicians.
For a full conference program, see the Motor Neurone Disease Association website (select News & Events, then Events, then Conferences).
Watch for further reports from the meeting in the March-April MDA/ALS Newsmagazine and read ALS Experts Gather to Exchange Ideas on the MDA/ALS Newsmagazine site.
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