Gene therapy of ALS
Gene therapy protects mice from Stephen Hawking disease for the first time
American biologists have developed a gene therapy that can stop the development of amyotrophic lateral sclerosis (ALS), a neurodegenerative disease that the famous astrophysicist Stephen Hawking suffered from. The first results of its successful application in mice are reported by the press service of the University of California at San Diego with reference to a publication in the scientific journal Nature Medicine (Bravo-Hernandez et al., Spinal subpial delivery of AAV9 enables widespread gene silencing and blocks motoneuron degeneration in ALS).
"Currently, there are no more effective forms of therapy aimed at combating ALS than those associated with the appearance of mutations in the superoxide dismutase-1 (SOD1) gene. In this case, our success also means that our method of delivering gene therapy to the spinal cord can be used to combat other types of ALS and other neurodegenerative diseases," commented Martin Marsala, one of the authors of the work, professor at the University of California at San Diego.
ALS is a severe incurable disease of the central nervous system, which leads to paralysis of the limbs and muscle atrophy. Various chemicals and therapies can only slightly slow down the development of the disease, and scientists still do not know the exact causes of its occurrence.
As a rule, patients suffering from ALS die from lung failure 2-5 years after diagnosis. Only British astrophysicist Stephen Hawking and his compatriot, guitarist Jason Becker, were able to avoid a similar fate due to the fact that the course of the disease slowed down dramatically. The scientist resisted it for more than half a century, gradually losing all remaining mobility, until he died in March 2018 due to respiratory arrest.
Correction of genetic typos
Approximately 5-10% of its carriers, as Marsala notes, suffer from a special hereditary form of ALS, the development of which is presumably due to the fact that mutations appear in the SOD1 gene, which is responsible for the production of antioxidants and the purification of cells from chemically aggressive molecules. Damage to even one of the copies of SOD1 leads to the fact that motor neurons gradually die due to the accumulation of "garbage" inside them, which leads to the development of paralysis and muscle atrophy.
In recent years, geneticists have repeatedly tried to create retroviruses that can "remove" a damaged copy of SOD1 and protect humans or animals from the development of ALS. However, all trials of such gene therapies ended in failure. They either did not act on experimental animals at all, or only temporarily slowed down the disease, but did not stop it.
Marsala and his colleagues solved this problem by creating a set of short RNA molecules that suppress the mutant version of SOD1. They also found a point in the soft shell of the brain that needs to be affected with gene therapy. As shown by preliminary experiments on healthy mice and primates, the introduction of the virus into this region of the nervous system contributed to the fact that it spreads as quickly and evenly as possible through motor neurons in the spinal cord and brain.
To test the effectiveness of this gene therapy, scientists raised mice that suffered from this form of amyotrophic lateral sclerosis and divided them into two halves. Scientists introduced the virus to the first batch of rodents even before the first symptoms of the disease appeared, and the second – after its development.
As this experiment showed, the virus successfully protected the first group of mice from the development of the disease and completely stopped the destruction of motor neurons that had not yet died in animals that suffered from ALS. At the same time, scientists have not recorded any negative side effects from the use of gene therapy throughout virtually the entire life of rodents, as well as during the first preliminary experiments on healthy pigs.
In particular, all rodents from the control group died about 300 days after the start of the experiment from respiratory arrest. At the same time, all individuals who received gene therapy lived for more than 460 days and did not experience health problems until the very end of the experiment. Now scientists are planning to test this gene therapy on monkeys and other large mammals to assess whether it is safe for humans.
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