Duchenne Gene Therapy

One injection of CRISPR/Cas9 relieved mice from myodystrophy

Maxim Abdulaev, "The Attic"

Scientists from Duke University edited the genome of mice with Duchenne myodystrophy. After the procedure to correct the wrong gene, the mice were cured, and the results have been preserved for a year, and observations of them continue. Article by Nelson et al. A long-term evaluation of AAV-CRISPR genome editing for Duchenne muscular dystrophy is published in the journal Nature Medicine.

Duchenne myodystrophy is a genetic disease that is caused by a mutation in the dystrophin protein gene. Dystrophin is involved in the creation of a protein complex that connects muscle fibers with the surrounding tissue. Due to a mutation in the dystrophin gene, the muscles degrade – the patient is confined to a wheelchair, suffers a lot and, as a rule, dies before the age of 30.

Scientists have tried to cure mice with myodystrophy from the disease. To do this, they took a model line of animals, mdx mice, in which an amino acid was specially removed in the dystrophin gene, which leads to the production of non-working dystrophin. In addition to mice, the experiment involved viral vectors that delivered the CRISPR/Cas9 system to mouse cells. The system had to cut out the area that carried the mutation. The mice were divided into three groups – a control group and two experimental ones. In one experimental group there were animals at the age of eight weeks (for humans it is about 4.5 months) – they were given intramuscular injections with a vector. In the second, mice two days old were injected with the same vectors intravenously.

The subjects were regularly tested for the content of edited genes and a serviceable protein. During a year of observations, the edited mice confidently continued to synthesize the corrected, working version of dystrophin. Muscle tissue synthesized dystrophin, slightly shorter than normal, but without the myodystrophy-causing mutation.

Nevertheless, not all mice perceived the changes in the same way: in those who received an injection at the age of eight weeks, the level of corrected copies of the gene gradually decreased, falling four times in six months, whereas two-day-old mice who were injected with "molecular scissors" intravenously increased the number of copies with the corrected gene after the same six months, even if and only by a few percent.

In addition, the scientists found that in mice treated in adulthood, the introduction of a foreign protein triggered an immune system response – the number of T-lymphocytes increased. The immunity of two-day-old mice, on the contrary, did not react to the intrusion of the CRISPR/Cas system in any way. However, the mice edited in childhood somehow, but produced a serviceable protein.

Scientists believe that it is too early to rejoice, because it is unknown how the human immune system will behave in the same situation. Nevertheless, the success itself on model organisms gives hope for the cure of patients with Duchenne myodystrophy in the future.

Yesterday it also became known about parallel attempts by scientists to create a gene therapy based on CRISPR/Cas: other biologists tried using this system to prolong the life of mice with Hutchinson-Guilford progeria. They lived a quarter longer than the control ones, but for some reason they died of sudden constipation.

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