Research Roundup updates as of December 2006:
The 17th International Symposium on ALS/MND (Amyotrophic Lateral Sclerosis/Motor Neurone Disease), held in Yokohama, Japan, Nov. 30 through Dec. 2, showcased important research findings, many of which involved MDA research grantees and clinicians. News items from the meeting are marked with [ALS/MND IS].
Report concludes military tie deserves further study
One high-quality study, with adequate allowance made for possible confounding factors, and three studies with some methodological limitations that make them less valuable, all support a relationship between having served in the military and later developing ALS, says a report released Nov. 10. A fifth study, also with limitations, failed to find such an association.
The report is from the Institute of Medicine of the National Academy of Sciences, which describes its role as providing "independent, objective, evidence-based advice to policymakers, health professionals, the private sector, and the public." It was requested by the Department of Veterans Affairs.
The Institute concludes "there is limited and suggestive evidence of an association between military service and later development of ALS." It recommends that the Veterans Affairs Department identify all possible ALS risk factors relevant to military service; conduct systematic reviews of the literature on these factors; and conduct further studies to uncover risk factors relevant to military service.
You can read more of the report or purchase the entire text by clicking on "Amyotrophic Lateral Sclerosis in Veterans" at www.iom.edu.
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Nonviral gene delivery comes of age
Delivering genes to the nervous system or muscles using a patented high-pressure injection system may be the "next big thing" in gene therapy, if MDA grantee Jon Wolff's hunch is correct.
Wolff, an MDA grantee at the University of Wisconsin-Madison, has been working with Mirus, a Madison biotechnology company, to develop gene delivery methods that don't require the use of viruses.
In October, Mirus announced it has a European patent on its gene-delivery approach, known as Pathway IV, which stands for "intravascular." The company received a U.S. patent for the technique in 2003.
Wolff says that, although the nonviral technique Mirus has patented can get genes into a large number of cells, "one of the concerns has been its safety, since it requires high intravascular pressure in order to be effective. However, we have conducted an extensive number of safety studies, and the technique appears to be very safe."
In ALS, candidates for gene therapy include genes for neurotrophic (nerve-nourishing) factors, such as VEGF and IGF1, and compounds that block toxic genes, such as SOD1 genes with ALS-causing mutations.
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FDA withholds approval of pseudobulbar affect drug
The experimental drug Zenvia (referred to as Neurodex until recently), developed by Avanir Pharmaceuticals of San Diego for the treatment of unwanted emotional expression, won't be approved by the U.S. Food and Drug Administration until additional data on safety and effectiveness have been supplied, according to an Oct. 31 press release from Avanir.
The company had hoped to market the drug for the treatment of "involuntary emotional expression disorder" (IEED), a condition associated with certain types of brain injuries and neurologic disorders, including ALS. (The phenomenon, which involves episodes of uncontrollable laughing or crying, is also known as pseudobulbar affect, and is thought to occur because of changes in signaling pathways in the brain.)
Zenvia is a combination of dextromethorphan, which affects signal transmission in the nervous system, and quinidine, which is said to help the body use dextromethorphan more effectively. In 2002, a trial that included 140 people with ALS showed the drug reduced the frequency of IEED episodes and improved quality of life.
The Oct. 31 press release said Avanir anticipates scheduling a meeting with the FDA to discuss the agency's additional requirements.
In addition, the release noted, Avanir "cannot be certain that once it has met with the FDA, that it will choose to continue with the development of Zenvia as previously planned."
"Unfortunately, it seems we may still have more work to do," said James Berg, who was vice president of clinical and regulatory affairs at Avanir until he left the company in November. "It makes me sorry for all of the people that could use this drug and need it."
The current clinical trial of Zenvia, open since 2003, will remain open until at least March 1, the company says. (See Clinical Trials at www.clinicaltrials.gov; or call Avanir at  622-5200.)
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Is generic Rilutek on the way?
Impax Laboratories of Hayward, Calif., announced Nov. 22 that it was one step closer to being able to market a generic version of Rilutek (riluzole), the only drug approved by the U.S. Food and Drug Administration for the treatment of ALS.
The drug interferes with glutamate, a carrier of signals in the nervous system. Sanofi-Aventis, headquartered in Paris, now holds a patent on the medication.
In November, the U.S. Court of Appeals for the Federal Circuit reversed an earlier decision by a district court that had prevented Impax from entering the riluzole market. It then redirected the case back to the district court. Impax, its Nov. 22 announcement says, "expects to request that the injunction preventing [it] from launching its generic version of Rilutek be lifted upon return of the case to the lower court."
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Direct delivery gets around baclofen sedation
Weakness and paralysis are what first come to mind when thinking about ALS. But for some patients, spasticity and cramps can also be a problem and can cause considerable discomfort or pain. Unfortunately, oral medications for these can have sedative side effects at the necessary doses.
A group from the MDA/ALS Center at Carolinas Medical Center in Charlotte, N.C., reported that the antispasticity drug baclofen can be delivered directly into the spinal fluid of ALS patients via a pump placed in the abdomen, and that this form of delivery avoids the side effects of oral medication. They studied 20 people with ALS who couldn't tolerate oral medication and who found they were able to reduce or eliminate their oral drugs once they were on the baclofen pump. There were no complications associated with pump insertion. [ALS/MND IS]
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Stimulating the diaphragm may have merit after all
Stimulation of the diaphragm muscle to improve breathing in people with ALS has had a controversial history. The technique involves implanting in the diaphragm electrodes that send signals through the phrenic nerve, which controls the muscle. Experts' objections have been based on the known progression of nerve cell loss, including in the phrenic nerve, in this disease.
Now, however, Raymond Onders and colleagues at Case Western Reserve University in Cleveland report that the strategy has been beneficial in eight people with ALS, slowing their decline in respiratory function as measured by forced vital capacity (FVC). There were no deaths and no tracheostomies in the treated patients.
Jeffrey Rosenfeld, who directs the MDA/ALS Center at Carolinas Medical Center in Charlotte, N.C., also tested phrenic nerve stimulation and found it beneficial in two out of the three ALS patients in this small study. Declining FVC stabilized, use of noninvasive ventilation decreased, and the patients assessed their functional ability as greatly improved. [ALS/MND IS]
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Selecting early responders may speed drug testing
|Identifying trial participants whose loss of function curve has changed by one to two units may streamline treatment testing.
It's now clear that ALS is a heterogeneous disease, and it's unlikely that any single treatment will work for everyone. But at this time, it's hard to know which treatments will work for which patients. Some researchers are trying to overcome this problem by altering study designs.
Findings from the Forbes Norris MDA/ALS Research Center at California Pacific Medical Center in San Francisco suggest that a subset of participants in a trial who can be classified as "responders" to a treatment might be identified by measuring a decrease in the slope of their loss of function.
The report suggests that participants who have a one- to two-unit change in the slope of their ALS Functional Rating Scale scores (indicating a slowing of disease progression) might be selected to form the basis of a smaller clinical trial, one in which nonresponders to the study drug wouldn't be able to obscure its possible benefits. [ALS/MND IS]
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