Gene knockout extends life of mice with ALS
Deleting a single gene almost doubles lifespan.
Knocking out a single gene nearly doubles the lifespan of mice with the animal model of Lou Gehrig's disease, suggesting that the gene may one day become a target for therapies in humans.
Lou Gehrig's disease, otherwise known as amyotrophic lateral sclerosis (ALS), is a neurodegenerative disease that gradually erodes motor control. Death usually follows within three to five years of diagnosis. There is no cure, and the only drug available that slows progression of the disease, riluzole, prolongs survival only by a few months.
Mice develop ALS-like symptoms when they have a mutation in a gene called SOD1— a mutation that causes about 1-2% of human ALS cases. Research using these animal models has suggested that chemically reactive forms of oxygen that can damage cells also contribute to the disease.
Several proteins present in the bodies of mice and people are known to generate reactive oxygen species as part of their normal function in cell signalling and inflammation. So John Engelhardt and his colleagues at the University of Iowa in Iowa City decided to look closely at two of these — Nox1 and Nox2 — to see whether turning down the amount of such proteins could slow the progression of ALS symptoms.
It did — dramatically. The team found that ALS mice lacking the gene that creates Nox2 produced fewer reactive oxygen species and lived on average for 229 days — 97 days longer than those who had normal levels of Nox21.
In an unexpected twist, many of the mice that lacked Nox2 also suffered from aggressive eye infections that, if left untreated, were often fatal. The reason for this is not known.
Eliminating the gene for Nox1 also extended lifespan, but only by 33 days. These results are still exciting, says neurologist Serge Przedborski of Columbia University in New York, because Nox1 is expressed, in part, in blood vessels, and there are hints that something might be going on in these vessels that affects the disease.
Work published last year by Przedborski also showed that eliminating Nox2 prolongs life in ALS mice, but the effect found in that research was much smaller: the mice only survived an additional 13 days2. Differences between the two results could stem from the different genetic backgrounds of the mice used, says Engelhardt.
Przedborski says the new results are encouraging. The relatively small increase in lifespan that he had previously observed had discouraged his research team from pushing towards human trials. "In light of this paper, I think we probably were wrong," says Przedborski. The new data make a stronger case for pursuing Nox2-targeting drugs, he says.
The results are potentially valuable for designing new therapies, agrees neurologist Jeffrey Rothstein of Johns Hopkins University in Baltimore, Maryland, but researchers should use caution before extrapolating from mice to humans. More than 100 drugs have been studied in ALS mice, many of which increased survival. About a dozen of those have been tested in humans, but so far only riluzole has proven consistently effective.
And then there are the lessons learned from minocycline, an antibiotic that performed better than riluzole in mice, yet worsened symptoms in humans. Minocycline dampens the activity of neuronal immune cells called microglia. Nox2 is also expressed in these cells, and that, says Rothstein, should raise a red flag about drugs that reduce Nox2 expression.
That's true, says Engelhardt. But minocycline also had very broad anti-inflammatory activity, and a drug that targets a single gene, such as Nox2, may not produce the same side effects. "Specificity for any drug is key," he says.
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