Edited mice have forgotten how to age
And at the same time – to defecate
Polina Loseva, "The Attic"
Hutchinson-Guilford progeria is one of the genetic diseases in which patients age so rapidly that they die, as a rule, already in adolescence. Two international teams of scientists have tried to cope with this disease in model mice using the CRISPR-Cas9 system. In both experiments, the animals lived a quarter longer than the controls, but could not recover completely. In addition, they began to die in a different way, probably due to problems with editing neurons.
There are several known syndromes of accelerated aging. They can manifest themselves both in childhood and in adulthood, and affect both the entire body and its individual parts (for example, the skin). The most common of them, Hutchinson-Guilford pediatric progeria, is caused by new mutations in the LMNA gene encoding lamins. These proteins form the inner lining of the nucleus and are needed to properly position DNA in the nuclear space. Two protein variants are obtained from the LMNA gene – lamin A (longer) and lamin C (shorter). Normally, lamin A splits to a shorter variant, but the mutation leads to the fact that it becomes impossible to split it. The mutant version of lamin A is called progerin: it accumulates in the nuclear membrane, deforming it and disrupting DNA stacking. The result is numerous mutations, DNA breaks, problems with repair of breakdowns and early death of patients. There is still no treatment other than symptomatic for progeria.
Yesterday, the journal Nature Medicine published the results of two studies (1, 2) devoted to the treatment of progeria. Both of them were carried out on a mouse model of the disease – animals with a characteristic mutation. In both cases, scientists used the CRISPR-Cas9 system to cut out a section of the gene responsible for lamin A without affecting lamin C, since it is known that mice completely devoid of lamin C are absolutely viable and do not show symptoms of progeria.
There were also small differences in the experiments: the researchers used different viruses to deliver CRISPR to cells, and also worked with mice of different ages, newborns or three-month-olds. Nevertheless, in both cases, the result was the same: a single injection of CRISPR prolonged the animals' life by a quarter (25 and 26.4%). At the same time, the mice in both experiments not only "lasted longer", but also began to feel better: their degeneration of muscles and subcutaneous fat stopped, they later began to lose weight and lose interest in grooming, and also retained the grip strength of the fore and hind limbs for longer.
However, it is too early to talk about a victory over progeria. Firstly, the life expectancy of modified mice is still far from their healthy relatives. Secondly, the editing efficiency remains low.
As the authors of one of the articles note, their CRISPR therapy worked best in liver cells. But she did not get to the lungs or kidneys, so the rejuvenation effect turned out to be uneven.
Finally, in one of the experiments, the researchers found that the edited mice did not die like ordinary patients: they did not fade away slowly, but suddenly died. At the same time, before death, they sharply lost weight and the ability to defecate, and at subsequent autopsies, they found bloating of the rectum and fecal masses solidified in them. Scientists suspect that the gene editing tools did not work in the metasympathetic nervous system, which regulates intestinal motility, so accelerated aging approached the mice from an unexpected side.
Yesterday it also became known about parallel attempts to create a gene therapy based on CRISPR/Cas: other biologists tried using this system to cure mice from Duchenne myodystrophy. After editing the genome, the mice were cured, and the effect did not disappear for a whole year of animal observations.
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