Rare Disease Report

CRISPR Used to Disable Defective Gene in ALS

JANUARY 04, 2018
Mathew Shanley
In historical studies, CRISPR/Cas9 technology has exhibited the ability to decrease the functionality of the mutant Dystrophin protein which has long been believed to be the underlying cause of Duchenne muscular dystrophy (DMD).

Recent data from scientists at the University of California, Berkley have found that the same gene editing platform can disable the defective gene responsible for amyotrophic lateral sclerosis (ALS), or Lou Gehrig’s disease, in mice. The therapy, which extended the lifespan of the mouse models by 25%, delayed the onset of the muscle wasting which characterizes the disease.

ALS is a degenerative neuromuscular disease and causes the loss of walking, talking, and swallowing in patients. When the muscles that control breathing fail, the condition becomes fatal. Approximately 20,000 Americans have been diagnosed with ALS, and there aren’t currently any approved treatments to halt muscle degeneration.

The mice used in the study were genetically engineered to express a mutated human gene that, in humans, is responsible for approximately 20% of all inherited forms of the disease and about 2% of all ALS cases around the world. The genetic cause for ALS is unknown, however, all are accompanied by the premature death of motor neurons in the brain steam and spinal cord.

The researchers at UC Berkley used a virus engineered by the team of the study’s senior author David Schaffer, a professor of chemical and biomolecular engineering and director of the Berkeley Stem Cell Center. The virus was used to seek out only motor neurons in the spinal cord and deliver a gene encoding the Cas9 protein into the nucleus.

The Cas9 was programmed to knock out only the mutated superoxide dismutase 1 (SOD1) gene, and as a result, the onset of the disease was delayed by almost 5 weeks, and mice treated by the gene therapy lived approximately 1 month longer than the typical 4-month lifespan of mice with ALS. Schaffer’s team is designing a version of the virus that will deliver the Cas9 gene to astrocytes and oligodendrocytes that should eliminate neighboring motor neurons.

Additionally, Schaffer is working on a self-destruct switch for the Cas9 protein that will allow for Cas9 to be eliminated from the cell after it knocks out the SOD1 gene. This will prevent the accidental modification of other genes, or an unintentional triggering of immune reactions.

“Being able to rescue motor neurons and motor neuron control over muscle function, especially the diaphragm, is critically important to being able to not only save patients, but also maintain their quality of life,” Schaffer said in an article in the Berkeley News. “I tend to be really cautious, but in this case I would be quite optimistic that if we are able to eliminate SOD1 within not just the neurons but also the astrocytes and supporting glia, I think we are going to see really long extensions of lifespan.”

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