CRISPR vs. "Hawking's Disease"
Gene therapy relieved mice of amyotrophic lateral sclerosis
Sergey Vasiliev, Naked Science
Amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease) became widely known thanks to Stephen Hawking, who suffers from this slow but incurable degradation of neurons, gradually losing more and more control over his own body. The exact etiology of the disease is unknown, but in some cases it can be associated with mutations in certain genes.
Gene therapy using CRISPR/Cas9 technology can give new hope to such patients. David Schaffer and his colleagues from the University of California at Berkeley talk about the new approach in an article published by the journal Science Advances (Gaj et al., In vivo genome editing improves motor function and extends survival in a mouse model of ALS).
The authors experimented with a GM line of mice carrying the mutant human superoxide dismutase-1 (SOD1) gene, which in humans is responsible for about 20 percent of cases of hereditary ALS (and 2 percent overall). It is these mutations in such patients that lead to the degradation of the motor neurons of the trunk and spinal cord, which continues with the degradation of muscle tissue, and in the final — and the inability to control the diaphragm and breathe.
As a vector – a point delivery vehicle – scientists used specially modified adenoassociated viruses, which in their usual form are practically safe for humans. The vectors delivered proteins and "corrected" CRISPR-Cas9 genes precisely to the motor neurons of the spinal cord. Proteins made incisions into the necessary sections of the genome, after which the cells' own repair systems themselves built new genes that no longer carry mutations into the vacant place.
In mice that underwent such experimental therapy, the signs of the disease developed noticeably slower, and on average they lived a month longer – not so little for the 4-month period prescribed for this GM line. A postmortem examination of the tissues showed that only those motor neurons survived in the spinal cord of such animals in which a successful gene replacement occurred. But, for example, astrocytes and oligodendrocytes supporting neurons, to which the vector was not directed, died almost completely.
Transverse section of the spinal cord: motor cells (yellow), in which the CRISPR/Cas9 system has worked, are highlighted with green fluorescent dye. Astrocytes (red) were not affected by gene therapy and died / ©David Schaffer
"Such a procedure has not yet made the BAS mice healthy, it is not yet a treatment," David Shaffer emphasizes. – But I think this is a strong "proof of principle" that CRISPR/Cas9 can become a therapy for ALS. When we perform additional optimization and are able to deliver CRISPR/Cas9 to most cells, we will see a further increase in life expectancy." Indeed, now Shaffer and his team are working on improving the viral vector in order to make it more versatile and deliver the gene drug also to the brain stem and other cells of the nervous tissue subject to degradation.
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