ALS Research Roundup February 2008

by Margaret Wahl on Fri, 2008-02-01 17:00
Illustration of chaperone molecules / 2008
Article Highlights:

Research Roundup updates as of January 2008

CytRx to test arimoclomol at higher dose

Merit Cudowicz
Merit Cudkowicz at Massachusetts General Hospital is one of the principal investigators for the arimoclomol trial.

Editor's note: On Jan. 22, CytRx announced that the Food and Drug Administration has placed a temporary hold on the arimoclomol trial while it reviews additional data from completed animal studies. See CytRx Provides Update on Phase IIb Arimoclomol Clinical Trial for ALS.

In December, the Los Angeles biopharmaceutical company CytRx announced it would compare its experimental compound arimoclomol at 400 milligrams three times a day to a placebo (inactive substance) in approximately 390 people with ALS at 30 to 40 North American centers.

The principal investigators on this CytRx-funded study are neurologist and MDA research grantee Merit Cudkowicz at Massachusetts General Hospital in Boston, and Jeremy Shefner, a neurologist and neuroscientist who directs the MDA/ALS Center at SUNY Upstate Medical University in Syracuse, N.Y.

Arimoclomol activates so-called chaperone molecules (see “Chaperone molecules,” below), which can repair damaged proteins or mark them for destruction. Damaged, misfolded and clumped proteins are known to play a role in familial ALS due to SOD1 gene mutations, and they’re likely to be detrimental to cells in other forms of the disease.

In June, CytRx announced that arimoclomol was safe and well tolerated at 100 milligrams three times daily and that function declined less rapidly in the arimoclomol-treated patients when they were compared to an earlier group of untreated patients.

Healthy volunteers have tolerated arimoclomol at 400 milligrams three times a day for 28 days and at 600 milligrams three times daily for a week.

For more information, contact Elizabeth Simpson at Massachusetts General Hospital at (877) 458-0631 (toll-free) or

Chaperone molecules
protein-cell illustration
Arimoclomol stimulates production of chaperone molecules, which attempt to maintain quality control by repairing damaged proteins; or, if they can’t, by tagging them for a cellular disposal system.

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Multinational study implicates DPP6 gene variant as risk factor for ALS

A specific variation in a gene known as DPP6 is significantly associated with susceptibility to ALS in a large group of people of European ancestry, says a study published online Dec. 16 in Nature Genetics.

When Leonard van den Berg at University Medical Center in Utrecht, the Netherlands, with colleagues in that country, as well as Belgium, Sweden and the United States, studied all the DNA of 1,767 people with ALS and 1,916 without the disease, they found that those with the disease were 1.3 times more likely than the unaffected subjects to have this particular variant in the DPP6 gene.

U.S.-based researchers in the group included Jennifer Schymick and Bryan Traynor of the U.S. National Institutes of Health in Bethesda, Md., and Roel Ophoff, of the University of California-Los Angeles.

The study participants were from the Netherlands, Sweden and Belgium.

DPP6 is located on chromosome 7 and carries instructions for a protein found mostly in the brain, where it modifies the biological activity of several nervous-system chemicals (neuropeptides) and alters a mechanism that controls potassium flow.

ALS is thought to be clearly inherited (familial) only about 10 percent of the time, but most experts in the disease believe that genetic factors alter susceptibility to sporadic (nonfamilial) ALS.

A recent study of this type (known as a whole genome association study) conducted at the National Institutes of Health failed to find any ALS-associated genetic variants. However, this past August, an MDA-supported whole genome study conducted at the Translational Genomics Research Institute in Phoenix identified a variant in a gene called FLJ10986 as a significant contributor to ALS susceptibility in a large sample of Americans with and without the disease.

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Protecting nerve-muscle junctions may protect nerve cells

Normal Neuromuscular Junction
Researchers say heat shock protein 70 could be acting at the junctions between nerve and muscle fibers.

Injections of a molecule known as “heat shock protein 70” allowed mice with a genetic form of ALS because of mutated SOD1 genes to live longer than untreated mice. These treatments also prolonged survival of nerve cells in the spinal cord and delayed the onset of ALS symptoms. Heat shock protein 70 is a molecular “chaperone,” and its normal role is to maintain quality control standards for cellular proteins (see “CytRx to test arimoclomol”).

Carolanne Milligan at Wake Forest University School of Medicine in Winston-Salem, N.C., led a research team that compared untreated mice destined to develop ALS with similar mice that were treated with abdominal injections of heat shock protein 70 three times weekly. They published their results Nov. 28 in the Journal of Neuroscience.

Although heat shock protein 70 and other proteins of its type are known to have protective effects on cells subjected to various stresses, the researchers expected that any protection against ALS-related damage would happen in the central nervous system.

To their surprise, they found that the protein ended up mainly in the skeletal muscles of the mice, not in the nerve cells, which have been assumed to be the primary sites of ALS damage. They say it’s possible that heat shock protein 70 could be acting in the periphery of the body, at the junctions between nerve and muscle fibers, rather than in the central nervous system, and that protecting these junctions may in turn protect nerve cells. Reducing neuromuscular junction damage “may prove to be an effective therapeutic target in ALS,” they note.

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Normal Neuromuscular Junction
The ALS Therapy Development Institute will work with Aptagen of Jacobus, Pa., to develop molecular bullets targeting ALS-affected cells.

ALS TDI collaborating with Aptagen to develop ALS-specific ‘bullets’

The MDA-supported ALS Therapy Development Institute in Cambridge, Mass., has entered into an agreement with Aptagen of Jacobus, Pa., to develop constructs known as “aptabodies” that recognize and stick to molecules associated with ALS disease progression.

For many years, scientists have used antibodies, which are proteins made by the immune system, to home to and interact with specific proteins, for research and as treatments. Antibodies are highly useful, but they can only target proteins and generally require knowledge of the protein being targeted.

In contrast, aptabodies can recognize and stick to a wider range of molecular structures than just proteins and require no prior knowledge of their potential targets.

The investigators hope to use aptabodies to identify specific compounds unique to the ALS disease process and to make molecular “bullets” that take therapeutic agents to specific, ALS-affected tissues or cells after systemic injection.

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Laughing/crying episodes more common than once thought

A new study suggests that pseudobulbar affect (PBA), also known as involuntary emotional expression disorder (IEED), may be more common in ALS than previously believed.

PBA is characterized by episodes of uncontrollable laughing or crying that are out of proportion to or inappropriate to environmental triggers. It’s thought to be a result of brain changes that can occur in ALS and other neurological disorders.

Jennifer Murphy, a psychologist at the University of California at San Francisco who presented her group’s findings at an international ALS meeting in December, determined that 52 percent (15 out of 29) of people with ALS who were not specially selected from a general ALS clinic population had PBA when a new questionnaire was used to assess them.

PBA is usually assessed using the Center for Neurologic Study-Lability Scale (CNS-LS), a seven-item, self-administered questionnaire that provides a measure of the perceived frequency of laughing/crying episodes.

On the CNS-LS, only 34 percent of this study’s sample (10 out of 29) were classified as having PBA.

Murphy and colleagues developed a more comprehensive questionnaire, which they call the PBAQ, which asks questions of both the person with ALS and his or her caregiver. Murphy said the PBAQ may help identify people with PBA who lack insight into their behavior.

Avanir Pharmaceuticals is testing a new medication directed at PBA (see “Avanir opens phase 3 trial” below).

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Avanir opens phase 3 trial of PBA drug

Avanir Pharmaceuticals in Aliso Viejo, Calif., has opened a large-scale (phase 3), multicenter study of its drug Zenvia to people with ALS or multiple sclerosis who have uncontrollable episodes of laughing or crying diagnosed as PBA (see “Laughing/crying”). The compound has shown promise in earlier studies.

Participants will be randomly assigned to receive a placebo or Zenvia, which is a combination of dextromethorphan and quinidine, at one of two dosage levels for three months. They’ll keep diaries of their crying and laughing episodes and respond to questionnaires about their condition.

More information is available at or at (866) 740-4333.

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Anti-SOD1 compound on path to clinical trials

Timothy Miller at Washington University in St. Louis says his MDA-supported studies to test a compound that blocks the genetic instructions for SOD1 are moving ahead. Mutations in the gene for SOD1 cause ALS in 1 percent to 3 percent of people with the disease.

The compound, ISIS 333611, made by Isis Pharmaceuticals of Carlsbad, Calif., is known as an antisense oligonucleotide. In December, the U.S. Food and Drug Administration (FDA) granted orphan drug status to ISIS 333611, which gives Isis special economic incentives for its development.

As the year ended, Miller’s group had nearly finished toxicity studies in rats and said it plans to open a phase 1 trial for ALS patients with known SOD1 mutations by fall 2008, depending on the FDA’s reaction to the toxicity data.

“Without the grants that we have received, the project would not be moving forward or would be moving at a snail’s pace,” Miller said. “The MDA grant will allow us to bring this to human trials in the near future.”

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Margaret Wahl
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