CRISPR gene editing has been used to more than double the lifespan of mice engineered to have the premature ageing disease progeria, also greatly improving their health.
The results far surpassed expectations. Progeria affects many different organs in the body, and the team behind the work didn’t expect that correcting the mutation in a relatively low proportion of cells – 10 to 60 per cent – would have such a big effect. “We were quite amazed,” says David Liu at Harvard University.
Hutchinson-Gilford progeria syndrome is a rare condition caused when a mutation, which probably took place in the testes or ovaries of a child’s parents, results in a single DNA letter change in one of the two copies of the gene for the lamin A protein. This leads to the production of an abnormal protein called progerin that interferes with cell division and causes many symptoms of premature ageing. The average lifespan of children with progeria is 14 years.
Conventional gene therapy, which involves adding genes, cannot help. People with progeria still have one healthy copy of the lamin A gene – the problem is the mutant progerin protein.
The standard form of CRISPR gene editing, which involves cutting DNA with the Cas9 protein, can be used to disable the mutant gene. The trouble is that it often disables the healthy copy too, as well as causing other unwanted changes.
Liu’s team has been modifying the Cas9 protein so instead of cutting DNA, it changes one DNA letter to another, a process known as base editing. He and his colleagues have now used a CRISPR base editor to correct the single-letter change that causes almost all cases of progeria, first in skin cells taken from a person with progeria and then in mice with a human version of the lamin A gene.
A virus carrying the genes for the base editor was injected into the blood of 2-week-old mice – roughly equivalent to 5-year-old children, says Liu – with the progeria mutation. A single injection boosted the median lifespan from 215 to 510 days, and the treated mice were also far more active.
Because the mice had the human gene, exactly the same approach could be used in human trials. However, Liu’s team has already developed even more efficient base editors.
In November 2020, the US Food and Drug Administration approved the first-ever drug for treating progeria. In trials, it increased lifespan by an average of 2.5 years over the maximum follow-up time of 11 years. Liu thinks combining this drug with the CRISPR base editing will work well.
The findings also boost hopes that many other conditions could be treated through base editing. Half of all known disease-causing mutations involve a single-letter change, most of which can be corrected with existing base editors, says Liu.
Journal reference: Nature, DOI: 10.1038/s41586-020-03086-7
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