BIologists tend not to discuss experimental results on a handful of cells and a single lone mouse – very preliminary, very incomplete. David Liu of the Broad Institute therefore had no plans to present such findings, which he peeked over the shoulder of his graduate student, when he gave a high-profile lecture in 2018 at the National Institutes of Health about a form of the CRISPR genome editing system he invented.
Not that he hasn’t been tempted. Student Luke Koblan used the new intelligent form of CRISPR, called base editing, to alter a single pair of misspelled “letters” in the 3 billion DNA cells taken from children with progeria, a marked infamous and fatal genetic disease by aging. Koblan had done this work in laboratory dishes and had also corrected the mutation of progeria in a mouse carrying the human gene that, as a result, aged so rapidly that, in early childhood, it looked like a photo of Dorian Gray with mustaches.
Talking before his conversation with NIH director Francis Collins, who discovered the progeria mutation in 2003, Liu mentioned the results. Collins was amazed. You have to put that in your talk, Said Collins. When the NIH chief speaks, biologists listen – and in Liu’s case, they rush to the men’s room to update his talk on how a CRISPR base editor can be the long-sought cure for progeria. Not a treatment, like the canvasfarnib drug that was approved last November, but an immediate cure.
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Liu’s lecture led to a collaboration with Collins, the CRISPR base edition of 62 rats with progeria and, on Wednesday, the announcement that the study produced “far better results than anything we’ve tried,” said Collins . The basic editor was so good at repairing the progeny of the mice that half the animals lived 510 days – old age for the mice and twice as long as the untreated mice.
With such impressive results, “it could become therapy for [progeria] and perhaps other rare accelerated aging syndromes, ”said Wilbert Vermeij of the Oncode Institute in the Netherlands, an expert in aging biology who was not involved in the study.
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If the mouse results are confirmed in human tests, “it feels like something that could be a true genetic cure with a single injection,” and not a drug that children need to take a lifetime, said Dr. Leslie Gordon, a doctor who founded the Progeria Research Foundation after his son, Sam Berns, was diagnosed with the disease. (He died in 2014 at the age of 17).
There are only about 200 children with progeria in the world. Although they look healthy as babies, at 1 or 2 years old they are not growing, losing fat under the skin and developing vascular and other problems characteristic of 80-year-olds. They usually die by the age of 14 from stroke, cardiovascular disease and other diseases of old age. Cognitively normal, they know exactly what’s going on with them.
The cause of progeria is a single base pair TA in DNA, where a CG should be. The resulting mutant protein, called progerin, is poisonous to cells.
Base editors are made for this mutation: they convert one letter of DNA into a different one, in this case the mutant TA into healthy CG. And they do this without cutting the double helix, as the standard CRISPR does, which risks mutilating genes.
The scientists first placed a base T to C editor on cells donated by children with progeria, using a lentivirus to transport the genome editor to the cells; 90% of the cells had their DNA corrected. “We were really surprised that we were getting such a significant correction at a site that caused the disease,” said Liu. The cells began to produce healthy protein, called lamina A, and very little poisonous progerin, reported in Nature.
The cells on the laboratory plates are all very good, but Liu knew he needed to test the system on mice – far more of them than the only animal in Koblan’s initial experiment. Collins was so excited by the preliminary results that he invited Liu to collaborate – an offer that cannot be turned down, as NIH has the largest progeria mouse colony in the world.
The pandemic slowed things down – Collins had to send all his lab workers home from March to July, until they discovered shifts and safe practices – but soon dozens of rats with 3 and 14-day progeria were being injected with the editor the base by means of an adeno-associated virus near the eye or in the abdominal cavity. (Both sites connect to the circulatory system, and scientists wanted the basic editor to reach as many types of tissue as possible.)
After six weeks, 10% to 60% of the cells in different organs, from the aorta to the liver, heart, muscle and bone, have been successfully edited. But those numbers reduced the improvement. Smooth muscle cells within blood vessels “are usually a graveyard at six months,” said Collins. “Although mice with gene editing had only about 20% of those cells corrected, it looked like a 100% correction: the uncorrected cells had died, leaving only healthy cells with an edited base. We have never seen anything like it ”with any other experimental therapy with progeria.
CRISPR rats also looked better and moved better, and lived an average of 510 days versus 215 days for untreated rats. Children in Eiger BioPharmaceuticals’ recently approved canvasfarnibe clinical trial lived an average of 2.5 years, or nearly 20%, longer than untreated children.
Fourteen days in mice (the age at which injecting the basic editor had the best results) is comparable to 5 or 6 years in a child. While more research needs to be done before a clinical trial can be launched – on the one hand, Liu is still making improvements to the base editor – “we would be very disappointed if it ended up as just an article,” said Liu. He is a co-founder of grassroots publishing company Beam Therapeutics, which said in a statement that “it is actively working with research teams and the Progeria Research Foundation to explore options for moving grassroots editing technology to children living with progeria. . “
Collins is hopeful that the usual decades between curing rats and curing people may not apply here. “Progeria is such a painful disease that it attracts many people to work on it,” he said. And the record pace of development of the Covid-19 vaccine has made researchers everywhere question why clinical trials for cures cannot go faster: “We will see if we can jump over some obstacles,” he said.