Familial ALS Research Update

The state of research in the familial (inherited) form of ALS was the focus of a special one-hour Webinar presented by the ALS Therapy Development Institute (ALS TDI) on March 25, with reports by CEO & Chief Scientific Officer Steve Perrin.

Although familial amyotrophic lateral sclerosis (FALS) and the more common sporadic (no family history) form of the disease both progress in a similar manner once symptoms appear, the causes of sporadic ALS remain elusive, while a number of genetic mutations that cause FALS have been — and continue to be — uncovered.

Advances in technology are making it easier for scientists to probe the mechanisms that drive FALS, and the resulting new body of knowledge is revealing targets at which scientists can aim therapeutics – some of which already have moved into clinical trials specifically for FALS.

Greater understanding of the causes and potential treatments for FALS has implications for treating sporadic ALS as well.

What do we know about FALS?

The ALS TDI Webinar reviewed FALS by the numbers: 

  • Five thousand new cases of ALS are identified in the United States every year; approximately 30,000 people in the U.S. are living with ALS at a given time.
  • Ten percent to 20 percent of all ALS cases are familial.
  • More than 13 genes are known to be genetic causes of ALS; three genes most commonly cause FALS: superoxide dismutase 1 (SOD1), fused in sarcoma (FUS) and TAR DNA binding protein (TARDBP, or TDP43).
  • Twenty percent of FALS cases are caused by a mutation in the ALS1/SOD1 gene. There are more than 100 SOD1 mutations commonly associated with FALS.
  • Average survival time after FALS symptom onset is 2 to 3 years. Twenty percent survive 5 years; 10 percent survive 10 or more years.
  • There’s a 100 percent chance a person will get FALS if he or she has one of the familial genetic mutations responsible for the disease.

FALS research timeline

1993: Mutations in the SOD1 gene were identified as a genetic cause of FALS.

1996: The SOD1 mouse model of ALS was made available for research.

2006: Mutations in the TDP43 gene linked to the development of FALS.

2009: A TDP43 mouse model was developed. Analysis is needed to determine how closely the model mirrors human ALS.

2009: FUS mutations linked to FALS.

FALS genetics

"Genetic mutation is causation," Perrin said in the Webinar. "In many other diseases that's not always true, but in familial ALS causation is directly correlated with these underlying mutations. If you have the mutation, you're going to get the disease."

Perrin reported that the number of genetic mutations associated with FALS is growing as researchers find more sophisticated methods of uncovering them. So, although it's currently accepted that FALS accounts for somewhere between 10 percent and 20 percent of all ALS cases, new technological tools soon will help to identify cases now classified as sporadic as, in fact, familial. 

Perfecting preclinical therapeutic development

ALS TDI aims its preclinical (laboratory-based) therapeutic development efforts at an area that falls between basic disease research and clinical (human) research.

The starting point for ALS TDI researchers, Perrin said, is characterization of the basic pathways underlying the start of the disease and the way it progresses.

"Once we have a basic understanding of some of those pathways," Perrin said, "the next step is drug development. You want to develop the most effective drugs you can that will target those molecular pathways, and then you want to systematically and very rigorously test them in a preclinical model."

Preclinical models may be a mouse model of the disease, or some other organism such as a rat or nonhuman primate (monkey).

ALS TDI uses a particular variant of the SOD1 mouse model known as SOD1 G93A. The Institute has done a lot of work creating best practices for trial design using the SOD1 model. From a database they compiled with information on more than 20,000 animals, ALS TDI researchers identified potential pitfalls in preclinical testing and developed an optimized study design that eliminates so-called "noise," or "unrecognized variables," that may cloud study results.

When this standardized study design is followed, the SOD1 mouse model is well-suited to helping scientists learn about the pathways of the disease and for testing drugs in a systematic fashion before moving into human clinical trials, Perrin said. This is because it's "very well-characterized" and "has a predictable disease course, just like in man."

"We now know that there are a lot of different mechanisms involved from first onset of paralysis through that whole process," Perrin explained.

These include muscle wasting; retraction of axons at the neuromuscular junction; immunological attack on peripheral nerves and the central nervous system; and motor neuron loss in the spinal cord.

    "All of these things evident in the mouse model, we now know are evident in the human disease as well," Perrin reported.  

    The Institute also has begun establishing a colony of the recently developed TDP43 mouse model, with plans to characterize that model and use it in testing as well.  

    Moving forward with FALS research at ALS TDI

    Perrin pointed out that ALS, whether familial or sporadic, has what is called a "biphasic nature." That is, it demonstrates two very specific and separate phases: the asymptomatic phase before symptoms begin, and the symptomatic phase where onset of symptoms occurs and progression is set in motion.

    Importantly, Perrin noted, disease progression, not disease cause, is "what you can build drugs against," so ALS TDI works to develop therapeutics directed not at what triggers the disease, but at slowing or stopping it once it's started.

    What's come out of the Institute's efforts is a promising drug called ALSTDI-00846, an antibody that targets what is called the "costimulatory pathway." (For more information, see ALS Research: Disconnecting the Immune System.)

    "It's the first drug ALS TDI has ever tested that slows down muscle loss, slows down disease progression, slows down the decrease in neurological scoring, and it extends survival," Perrin noted. "It has quite a significant effect, which makes it quite exciting."

    FALS current clinical trials   

    Perrin reported on three trials getting under way that are aimed specifically at FALS.

    ISIS-SOD1-RX: Isis Pharmaceuticals of Carlsbad, Calif., has begun a phase 1 clinical trial of its experimental reagent ISIS-SOD1-Rx.

    It is hoped that ISIS-SOD1-Rx will block production of SOD1 protein through what is called "antisense" technology, in which certain instructions used in protein production are masked. Isis has generated supporting data for this strategy in both a mouse model and a nonhuman primate model. (For more on this trial, see ALS SOD1 Trial: A 'Watershed Moment'.)

    Arimoclomol: A phase 2/phase 3 study of a small-molecule drug called arimoclomol is under way to determine safety, tolerability and efficacy in people with FALS.

    Arimoclomol has been shown in cell culture experiments and in the SOD1 mouse model to reduce SOD1 protein in various tissues and improve the survival of motor neurons.

    Pyrimethamine: A phase 1/phase 2 trial of a drug called pyrimethamine aims to determine whether the drug can reduce the quantity of SOD1 protein in the cells of people with FALS.

    Pyrimethamine, available as a pill, is approved by the U.S. Food and Drug Administration to treat some parasitic infections. The trial is currently recruiting participants.

    Early investigator-initiated studies have generated promising results for this strategy in studies in cell culture, the mouse model, and in a small study of people with FALS. (For more information, see Anti-Malarial Drug Takes Aim at SOD1.)

    Coming up from ALS TDI

    ALS TDI's next 2010 Research Update Webcast is scheduled for 6 p.m. EDT, May 18.

    The Institute's next Web Exclusive, "How is ALS Research Funded?," will be broadcast at 6 p.m. Eastern Time, June 22.

    To see a complete schedule of ALS-related news and topics, as well as this and other archived Webcasts, Webinars and conference calls, visit the Institute's Web site at www.als.net and click on "Research."

     

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