ALS Research Briefs: FUS-TDP43, SOD1 Mutation and Webinars

by Amy Madsen on Fri, 2011-09-09 14:27

Research about FUS-TDP43 interaction, a newly identified SOD1 mutation, and historical controls in trials; and webinars about the TDP43 mouse and the ceftriaxone trial

Article Highlights:

Reports on ALS (amyotrophic lateral sclerosis) research including:

  • FUS and TDP43 normally work together to ensure long-term survival of motor neurons.
  • D11Y, a recently discovered ALS-causing mutation in the SOD1 gene, appears to cause a less-severe form of the disease.
  • Historical controls may help streamline clinical trials.
  • A special webinar Aug. 15, 2011, on the TDP43 ALS research mouse has been archived and is available for viewing on the ALS Therapy Development Institute website.
  • A webinar scheduled for Sept. 26, 2011, will enable viewers to learn about an ongoing phase 3 trial of ceftriaxone in ALS.

FUS and TDP43 work together in fruit flies

In a fruit fly research model of inherited ALS, human FUS and TDP43 proteins work together on some processes necessary for the long-term survival of muscle-controlling nerve cells (motor neurons), reports a research team at Columbia University Medical Center in New York.

When the genes for either of these proteins is mutated (flawed), the investigators found, interaction between the two proteins is impaired, causing disruption of the critical molecular processes that require their collaboration.

The researchers, led by Brian McCabe at Columbia University's Center for Motor Neuron Biology and Disease, published their findings online Sept. 1, 2011, in the Journal of Clinical Investigation. (Read their paper online at no cost: The ALS-associated proteins FUS and TDP43 function together to affect Drosophila locomotion and life span.)

FUS and TDP43 are known to have numerous functions, many of which involve RNA processing (the chemical step that precedes protein building). Abnormalities in the genes for FUS and TDP43 have been linked to human ALS.

Initially, the research team created a fruit fly model with a FUS-associated ALS-like disease, and found that the flies had impaired mobility and reduced life span when compared to normal flies.

In a series of experiments, the team was able to "rescue" (return to normal) the flies with abnormal FUS genes via insertion of normal human FUS genes. Insertion of human FUS genes containing an ALS-causing mutation did not result in any improvement of symptoms in the flies.

Flies with mutated TDP43 genes showed deficits in survival and motor function similar to those in flies with mutated FUS genes. The flies with mutated TDP43 genes were rescued with insertion of normal human TDP43 genes (and not with mutated human TDP43 genes).

Next, the team attempted to "cross-rescue" the flies with mutated TDP43 or FUS by increasing production of normal FUS protein in flies with abnormal TDP43 and of normal TDP43 protein in flies with abnormal FUS.

The investigators found that this cross-rescue technique only worked in one direction: Increased activity of normal FUS protein rescued flies with TDP43 mutations, but overproduction of normal TDP43 protein did not rescue flies with FUS mutations.

The new findings have potential implications for development of therapies.

"One could imagine that if you could develop a drug or gene therapy that could make FUS more active, it might [also] help in patients who have TDP43 mutations," McCabe said in a press release issued by Columbia University Medical Center.

"Our results show that these two genes work together in a familial ALS model," McCabe added, noting that it's important to discover how ALS-related genes and proteins cause the disease and if and how they work together.

"The hope is that if we can eventually understand how all ALS genes interact, we can figure out how to intervene."

The ALS lithium trials: Lessons learned

The use of an historical control group in an MDA-supported trial of lithium in ALS has proven successful, and further use of this type of control may result in more efficient phase 2 trials for screening ALS therapies in the future, a research team has reported.

A historical control group is made up "on paper," using data taken from a group of patients who don't physically participate in a current trial, but who were observed (oftentimes in another trial) in the past. The historical controls are matched to current trial participants with respect to variables such as age, gender, type of onset, rate of disease progression and use of riluzole (the only drug approved for treatment of ALS by the U.S. Food and Drug Administration).

The investigators, including neurologist and study director Robert Miller, who co-directs the Forbes Norris MDA/ALS Center at California Pacific Medical Center in San Francisco, reported their findings online Aug. 3, 2011, in Neurology. (See Phase II screening trial of lithium carbonate in amyotrophic lateral sclerosis: Examining a more efficient trial design.)

The MDA trial was among several initiated after a 2008 report from a small trial in Italy suggested that lithium carbonate (commonly used to treat bipolar disorder) might slow the progression of ALS.

In fact, results from the trial, reported at the April 2010 meeting of the American Academy of Neurology, showed that the drug failed to slow progression of the disease; side effects were numerous and sometimes serious; and rate of decline as measured by the ALS Functional Rating Scale-Revised (ALSFRS-R) was greater in 107 patients taking the drug than that in 249 historical control patients.

The investigators selected from a database of 616 historical controls who received a placebo in six earlier trials. They tested multiple control groups and determined that there was no significant variance in results.

In an accompanying editorial, Historical controls in ALS trials: A high seas rescue?, also published online Aug. 3, 2011, in Neurology, neurologists Peter Donofrio and Richard Bedlack suggest trials designed to use historical controls may be more "resource-efficient." (Donofrio is the director of the MDA/ALS Center at Vanderbilt University Medical Center in Nashville, Tenn., and Bedlack is the former director of the MDA/ALS Center at Duke University Medical Center in Durham, N.C.)

"There is no question that phase 3, randomized, placebo-controlled trials remain the gold standard for determining the efficacy and long-term safety of a therapy," Donofrio and Bedlack wrote. But "creative" and "efficient" phase 2 studies can help researchers select the most promising experimental treatments to advance into resource-intensive phase 3 testing.

The authors caution that historical controls must be well-matched to trial participants. "Contemporary" controls from more recent studies can help ensure that in addition to physical characteristics, a shift in treatment standards (such as the trends toward earlier feeding-tube placement and respiratory support) will be equally represented in both the treatment and control groups.

The data from the lithium trial, Donofrio and Bedlack noted, "make a strong argument" for using carefully matched contemporary historical controls to expedite drug screening and the development of ALS therapies.

D11Y mutation in SOD1 gene causes 'benign' form of ALS

A recently discovered ALS-causing mutation in the superoxide dismutase 1 (SOD1) gene appears to cause a less-severe form of ALS, reports a team of researchers in Rome.

The research team, including corresponding author Mario Sabatelli at the Institute of Neurology, Catholic University of Sacred Heart, Rome, described its findings online Aug. 11, 2011, in the Journal of the Neurological Sciences. (See D11Y SOD1 mutation and benign ALS: A consistent genotype-phenotype correlation.)

More than 150 ALS-causing mutations in the SOD1 gene have been identified to date (see the SOD1 Gene Overview at the ALS Online Genetics Database), but robust associations between particular mutations and specific disease characteristics are not always apparent.

The investigators studied the D11Y mutation in the SOD1 gene and its effects in three people with ALS. They found that the mutation causes a form of ALS characterized by "predominant involvement of the distal muscles [those of the lower arms, hands, lower legs and feet] and a very slow progression of the disease."

Such an association between a particular genetic mutation (genotype) and the resulting manifestation in an animal or person (phenotype) is called a genotype-phenotype correlation.

Known correlations can help physicians speed diagnosis and predict disease course.

"The most important implication of our findings is diagnostic," Sabatelli confirmed, noting that testing for the mutation can now be used to help make a diagnosis in people with an atypically slow form of ALS. The unusually slow clinical course of the disease, he added, is "fundamental information for patients."

In addition, learning how the D11Y SOD1 mutation results in this relatively benign form of ALS may help scientists determine the mechanisms by which SOD1 mutations kill motor neurons, Sabatelli said.

Such valuable insight into the disease process potentially may inform future development of therapeutic strategies.

ALS TDI: Webinar on TDP43 mouse available for viewing

A special webinar on the TDP43 ALS research mouse model has been archived and is available for viewing.

The Web-based seminar originally was webcast Aug. 15, 2011. It was hosted by the MDA-supported ALS Therapy Development Institute (ALS TDI), a nonprofit biotech headquartered in Cambridge, Mass., that has partnered with MDA since 2007 in the fight to stop ALS.

Featured speakers were Bob Baloh, an assistant professor of neurology at Washington University School of Medicine in St. Louis; and Fernando Vieira, ALS TDI director of in vivo operations.

Baloh, who serves on MDA's Medical Advisory Committee and has an MDA research grant to study TAR DNA-binding protein 43 (TDP43), coordinated the research team that developed the TDP43 ALS research mouse. The mouse carries a mutation in the TDP43 gene and is expected to broaden scientists' knowledge of ALS disease progression and the effects of experimental treatments. It should complement what has already been observed in the most widely used ALS model to date, a mouse that carries mutations in the gene for superoxide dismutase 1 (SOD1).

Over the past several years, a growing body of evidence has suggested that some ALS-causing mutations cause the TDP43 protein to mislocalize outside where it normally resides in the cell nucleus. Some research has linked this abnormal protein activity to both familial (inherited) as well as noninherited, or sporadic, ALS.

The approximately 90-minute webinar provides an inside look into what TDP43 is, why it's important, the development of the TDP43 mouse, and an update on where the ALS TDI team is in determining the characteristics of the model.

To access the webinar, click on the link at the top of this item, click on "Get Involved," and then "Webinar: The ALS Crisis." On the right-hand side of the page, find the information and link for the webinar, "TDP43 Mouse Model: What have we learned?" (Registration is required.)

Upcoming Webinar: Ceftriaxone trial in ALS

A webinar (Web-based seminar) about an ongoing phase 3 clinical trial of ceftriaxone in ALS is scheduled for Sept. 26, 2011, from 2 to 3 p.m. ET.

Webinar hosts will be neurologist Merit Cudkowicz, the principal investigator for the trial and director of the MDA/ALS Center at Massachusetts General Hospital in Boston; and Jeremy Shefner, professor and chair of neurology at Upstate Medical University, State University of New York in Syracuse, and director of the MDA/ALS Center at that institution.

Cudkowicz and Shefner will explain the scientific rationale behind the trial and describe the study procedures. Both will be available to answer participants' questions.

Ceftriaxone is an antibiotic that may confer neuroprotective benefits to the motor neurons (nerve cells) that die off in ALS.

The first two stages of the clinical trial of ceftriaxone in ALS have been completed. The aim of stage 1 was to determine the pharmacokinetics (way the body absorbs, distributes, metabolizes and excretes a drug) of ceftriaxone at 2 grams and 4 grams per day. The goal of stage 2 was to determine the 20-week safety and tolerability of ceftriaxone.

The efficacy portion of the study, called stage 3, is ongoing and researchers currently are recruiting participants for the trial at more than 60 locations across the United States and Canada. The aim of this phase of the study is to determine if ceftriaxone prolongs survival and/or slows decline in function in ALS.

Those interested in viewing the webinar may still register. (The program will ask that you enter your first and last name upon registration. In the interest of privacy, it's recommended participants enter initials only or first name and last initial.) Early registration is recommended, as space is limited.

Call-in information will be available for participants in the United States and Canada.

To read more about the study, visit the ceftriaxone study page on the Northeast ALS Consortium (NEALS) website.

For more information on the upcoming webinar, or the trial, contact Sarah Titus, project manager, at, or (617) 726-1398.

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