Blocking a Protein Extends Survival in ALS Mice

Elevated levels of an immune-system protein called interleukin-1-beta (IL-1-beta) exacerbates a disease in mice that closely resembles human amyotrophic lateral sclerosis (ALS), and blocking this protein extends survival in these mice, a research team in Germany has found.

The study adds to the accumulating evidence that the immune system misbehaves in ALS and that altering its behavior could be a way to treat the disease.

About the new findings

Arturo Zychlinsky and colleagues at the Max Planck Institute for Infection Biology in Berlin published the findings in the July 20, 2010, issue of Proceedings of the National Academy of Sciences.

The rodents in these experiments have a mutation in the gene for the SOD1 protein that causes the protein to become toxic. SOD1 research mice are a widely used "mouse model" of ALS.

Toxic SOD1 protein arising from mutated SOD1 genes is the cause of ALS in about 1 percent to 2 percent of human cases of the disease. However, many experts believe the SOD1-related form of ALS and other forms overlap considerably at the cellular and molecular levels, as well as at the more obvious symptom level.

The Berlin researchers found that toxic SOD1 protein apparently sends out a "danger signal" in the nervous system, alerting immune-system cells and causing them to produce excess quantities of mature IL-1-beta. Although inflammation via IL-1-beta is one of the body's many defense mechanisms, it unfortunately made the disease process worse, rather than better, in this situation.

When the researchers blocked IL-1-beta with a protein called IL-1 receptor antagonist (a blocker of IL-1-beta action), they found the mice survived significantly longer than placebo-treated mice.

The 19 mice with an SOD1 mutation and an ALS-like disease that were treated with a placebo lived an average of 153 days. The 23 SOD1 mice that received 75 milligrams per kilogram of body weight of the IL-1 receptor blocker survived an average of 158 days. And the 21 mice receiving 150 milligrams per kilogram of the receptor blocker survived 159 days, on average.

Those numbers may not sound like the treatment made much of a difference, but the researchers noted that the differences in survival time were statistically significant, meaning it's extremely unlikely that the results were due to chance. With dosage adjustment and other refinements, the outcomes might be better.

In an accompanying editorial, Jos van der Meer and Anna Simon of Radboud University Nijmegen Medical Centre in the Netherlands noted that elevated concentrations of IL-1-beta have been detected in the spinal fluid and spinal cords of ALS patients, including those with non-SOD1-related ALS.

They said a medication called anakinra is an IL-1-beta receptor blocker that has been used to treat humans, although its ability to enter the central nervous system (which may be necessary to treat ALS) is minimal. They said there are other drugs that also block IL-1-beta that have recently come on the market that could be investigated for their possible utility in ALS.

Meaning for people with ALS

There is increasing evidence that the immune system, perhaps in its attempt to protect the body from harm in the early stages of ALS, produces substances that ultimately prove harmful, accelerating, rather than slowing, the disease process.

Changing the immune system's behavior is looking like a viable therapeutic direction.

The MDA-supported ALS Therapy Development Institute, for instance, is developing a compound called ALSTDI-00846 to block a different immune-system pathway from the one the German team is targeting. (See ALS TDI: Full Speed Ahead.)

If a drug that is already approved for other conditions were to be tested in ALS, it would not have to go through as long a development phase as a brand new experimental compound.

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