ALS Research Roundup Sept.-Oct. 2009

by on Tue, 2009-09-01 10:43
Article Highlights:

ALS Research Roundup updates as of August 2009

This article reports on research news as of Aug. 31, 2009, on: ALS TDI * Iplex * ALS-PON * emotional symptoms * stem cells


ALS TDI reports quarterly progress

On July 16, 2009, the MDA-supported ALS Therapy Development Institute (ALS TDI, gave its quarterly research update in a Webcast that’s now archived on the Institute’s site and accessible to all who register (free).

Topics in the Webcast included the promising compound ALSTDI-00846; gene therapy; stem cells; barriers to drug development; and whether motor neurons are culprits or innocent bystanders in the ALS disease process.

MDA and the ALS TDI, in Cambridge, Mass., have collaborated to support ALS research since 2007.


The compound ALSTDI-00846 modifies a specific immune-system response, and has excited ALS TDI researchers because of its effects on ALS mice, said Steve Perrin, CEO and chief scientific officer at ALS TDI.

In studies of more than 200 mice, the compound increased survival an average of 12 days, said Perrin. Although that may not sound like much, Perrin said this is a “much bigger effect [in mice] than Rilutek,” the only drug approved by the U.S. Food and Drug Administration (FDA) for the treatment of ALS.

In addition, body weight in the mice increased, and the loss of neurological function slowed.

More about ALSTDI-00846 can be found on the ALS TDI Forum (

Gene therapy

Gene therapy, Perrin said, is “coming back into the limelight” after being derailed some 10 years ago by the death of a patient with a metabolic disease who was participating in a gene therapy trial.

ALS TDI is working with the biotech company Asklepios BioPharma of Chapel Hill, N.C., to develop gene therapies for ALS. (Asklepios has received MDA support to develop gene therapy for Duchenne muscular dystrophy.)

Stem cells

John McCarty, director of therapeutic investigations at ALS TDI, reported on the International Society for Stem Cell Research conference he attended this summer in Barcelona, Spain.

McCarty said stem cells have three basic applications in ALS: 1) as research tools; 2) as cell replacement therapies; and 3) as a vehicle for delivering therapeutic substances.

Other targets

McCarty emphasized that ALS is “not just about motor neurons,” the cells in the brain and spinal cord that control muscle action and that are lost in ALS. Other potentially important cell types that could be targeted to treat the disease may be glial cells (non-nerve cells in the nervous system), muscle fibers and cells of the immune system, McCarty said.

Perrin echoed these sentiments, noting that, “It can be difficult to get a drug into the central nervous system, so these other mechanisms open up therapeutic, drugable pathways.” (Muscle fibers are outside the central nervous system, and immune-system cells have multiple locations.)

He went so far as to say that motor neurons may in fact be innocent bystanders that become victims in the ALS disease process.

Barriers to drug development

“Traditional pharmaceutical industry assumptions about ALS” are barriers to drug development in the disease and need to be challenged, said Perrin.

The industry has been averse to developing treatments for ALS, he said, because it believes 1) there are not a lot of patients, so the market is small; 2) the cause of ALS is unknown; and 3) there is no biological marker (biomarker) that can be easily measured to follow the course of the disease or the response to treatment.

Perrin stressed the importance of educating commercial firms that the market for ALS is potentially as large as it is for multiple sclerosis (MS) and is made smaller because ALS is such an aggressive disease. “If we could get a molecule that impacts the disease in ALS,” he said, “the number of [living] patients is going to climb, as it did for MS.”

He said research at ALS TDI focuses on understanding the biological pathways involved in ALS and on defining biomarkers to follow the course of the disease. Progress, he emphasized, is definitely being made.

Next Webcast in October

The next quarterly ALS TDI research Webcast will take place Oct. 5, 2009, during the Institute’s Leadership Summit. Register for the quarterly Webcast at

Monthly Webinars are also offered by the ALS TDI.

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Iplex on hold

The Richmond, Va., biopharmaceutical company Insmed ( announced July 27, 2009, that it will not supply its experimental drug Iplex to any new patients with ALS for the foreseeable future, and that it intends to analyze the available data on Iplex for ALS and for myotonic dystrophy before deciding whether to proceed with development of the drug for either disease.

Iplex is a combination of the protein insulin-like growth factor 1 (IGF1) and IGF binding protein 3. Laboratory studies have suggested it may preserve muscle or nerve tissue under adverse circumstances, including degenerative disease.

There is no evidence that the drug is effective against ALS, but it has been available for use by ALS patients in other countries, and data so far suggest the compound is reasonably safe. According to Insmed, as of July 27, 2009, there were about 70 patients with ALS receiving Iplex, 12 in the United States and the remainder “around the rest of the world,” mostly in Italy.

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Meta-analysis finds no ALS-PON gene connection

The jury is still out on whether variations in PON genes, coupled with toxic exposures, such as some military personnel may have experienced during the Gulf War, raise the risk of ALS. (iStock photo)

A new report combining data from 11 studies has failed to find a connection between variants in genes for paraoxonase (PON) enzymes and an increased risk of developing ALS.

The report, published July 7, 2009, in Neurology, included Orla Hardiman at Beaumont Hospital in Dublin (Ireland), whose MDA-supported study of PON gene variations in Ireland was published in 2007.

PON genes are the instructions for PON enzymes, which play a role in detoxifying certain poisons, such as organophosphate-based pesticides.

PON gene variants, in conjunction with toxic exposures (such as may have been experienced by soldiers in the first Gulf War), have been suspected of increasing ALS susceptibility.

The new “meta-analysis” (an overall analysis of several studies) rules out a common PON genetic mechanism that raises ALS risk across worldwide populations.

However, the analysis does not rule out the possibility that PON gene variations may raise ALS risk in people living in specific areas or in those who have experienced specific environmental exposures. (For more on this subject, see “How Reliable Are Genetic Association Studies?”)

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Zenvia shows promise in treating ALS-related emotional symptoms

The pharamaceutical company Avanir has announced positive results for its phase 3 trial to treat unwanted episodes of laughing and crying in patients with ALS and multiple sclerosis using its experimental drug Zenvia.

This emotional phenomenon, known as “involuntary emotional expression disorder” (IEED) or “pseudobulbar affect” (PBA), is common in ALS and is believed to be caused by damage to an area of the brain the controls emotional expression. Contrary to appearances, people usually don’t feel emotional during a laughing or crying episode. (For an explanation of PBA and other ways to deal with it, see “PBA Symptoms No Laughing Matter,” MDA ALS Newsmagazine, March 2006.)

Zenvia (formerly called Neurodex) is a combination of two drugs, dextromethorphan and quinidine. Two dosage formulations were used in the trial: 30 milligrams of dextromethorphan combined with 10 milligrams of quinidine and 20 milligrams of dextromethorphan combined with 10 milligrams of quinidine. Avanir reports both dosages significantly reduced episodes of PBA compared to a placebo. The drug was generally safe and well tolerated.

The company intends to announce complete results from the phase 3 study this fall and to follow guidance from the U.S. Food and Drug Administration (FDA) to gain market approval for Zenvia to treat PBA.

For a thorough discussion of Zenvia in an Aug. 11, 2009, conference call, see “Webcasts” at

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Study emphasizes need for caution with stem cells

A new study shows mice receiving stem cell transplants from cells that were originally adult mouse cells were more likely to develop tumors than those receiving transplants derived from mouse embryonic stem cells.

There’s been a great deal of progress in the ability to induce adult cells to return to a stemlike state and then mature into specific cell types, including nerve cells. A goal of such research is therapeutic stem cell transplantation using immunologically compatible cells, taken from patients and then reprogrammed. However, new studies show caution is warranted.

Hideyuki Okano at Keio University in Tokyo and Sinya Yamanaka at Kyoto (Japan) University coordinated one study, publishing results online in Nature Biotechnology July 9, 2009.

Out of 34 mice that received neurologic stem cells derived from mouse embryonic stem cells, only three (9 percent) developed tumors. However, the story was different when the neurologic stem cells were derived from adult mouse cells that were then reprogrammed.

For instance, of 55 mice receiving induced stem cells derived from adult mouse tail cells, 46 (84 percent) developed tumors. And out of 36 mice receiving neurologic stem cells derived from mouse liver cells, 10 (28 percent) showed tumors.

The scientists believe tumor formation can be influenced by the tissue of origin for the induced stem cells and by the methods used for reprogramming the cells.

They concluded that “all of the variables affecting safety must be rigorously evaluated before therapies based on induced pluripotent stem cells advance to the clinic.” (For a discussion of current stem cell treatments being promoted for ALS, see "Stem Cells Abroad.")

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