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BIologists tend not to discuss the experimental results on a handful of cells and a single solitary mouse – too preliminary, too sketchy. David Liu of the Broad Institute therefore had no intention of presenting such findings, which he glanced over the shoulder of his graduate student, when he gave a high-level lecture. in 2018 at the National Institutes of Health on a form of the CRISPR genome. -the editing system he invented.
Not that he wasn’t tempted. Student Luke Koblan had used the smart new form of CRISPR, called Basic Editing, to modify a single pair of misspelled “letters” among the 3 billion DNA cells taken from children with the disease progeria. infamous and deadly genetics marked by aging. Koblan had done this work in laboratory dishes, and had also corrected the progeria mutation in a mouse carrying the human gene which, as a result, was aging so quickly that from a young age it was like a picture of Dorian Gray with some mustaches.
Speaking before his interview with NIH Director Francis Collins, who discovered the progeria mutation in 2003, Liu mentioned the results. Collins was blown away. You have to put that in your speech, Collins said. When the NIH chief speaks, biologists listen – and in Liu’s case, run into the men’s room to update his speech on how a CRISPR base editor might just be the long-sought cure for progeria. Not a treatment, like the drug lonafarnib which was approved last November, but a single cure.
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Liu’s intervention led to a collaboration with Collins, the CRISPR publishing base of 62 mice with progeria, and on Wednesday the announcement that the study was producing “results so much better than anything we’ve ever tried. Collins said. The Basic Editor was so good at repairing progeria in mice that half of the animals lived 510 days – an advanced age for mice, and twice as long as untreated mice.
With such astonishing results, “it could become a therapy for [progeria] and possibly other rare accelerated aging syndromes, ”said Wilbert Vermeij of the Oncode Institute in the Netherlands, an expert in the biology of aging who was not involved in the study.
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If the results from the mice are confirmed in human trials, “it sounds like something that could be a real genetic cure with just one injection”, not a drug that children have to take their entire lives, he said. said Dr Leslie Gordon, a physician who founded the Progeria Research Foundation after her son, Sam Berns, was diagnosed with the disease. (He died in 2014 at age 17).
There are only about 200 children with progeria in the world. Although they appear healthy as babies, by age 1 or 2 they fail to grow taller, lose the fat under their skin, and develop vascular problems and other features of their 80s. They usually die around the age of 14 from stroke, cardiovascular disease, and other diseases of old age. Cognitively normal, they know exactly what is happening to them.
The cause of progeria is a single TA base pair in DNA where a CG should be found. The resulting mutant protein, called progerin, is toxic to cells.
Basic editors are made for such a mutation: they convert one letter of DNA into another, in this case the TA mutant into a healthy CG. And they do this without cutting the double helix, like standard CRISPR does, which risks mutilating genes.
Scientists first slipped a basic T-to-C editor into cells donated by children with progeria, using a lentivirus to transport the genome editor into the cells; 90% of cells have had their DNA corrected. “We were really surprised to get such a big correction at such a pathogenic site,” Liu said. The cells began to produce healthy proteins, called lamin A, and very little toxic progerin, they reported in Nature.
The cells in the lab dishes are all good, but Liu knew he had to test the system on mice – much more than the solitary animal in Koblan’s initial experiment. Collins was so excited about the preliminary results that he invited Liu to collaborate – an offer not to be refused, since the NIH has the largest colony of progeria mice in the world.
The pandemic has slowed things down – Collins had to fire all of his lab workers from March through July, until they discovered shifts and safe practices – but soon dozens of progeria mice ages 3 and 14 days were injected with the base editor. via an adeno-associated virus near the eye or in the abdominal cavity. (Both sites connect to the circulatory system, and the scientists wanted the Basic Editor to reach as many tissue types as possible.)
After six weeks, 10% to 60% of cells from different organs, from the aorta to liver, heart, muscle and bone, had been successfully edited. But these numbers limited the improvement. Smooth muscle cells inside blood vessels “are usually a graveyard at six months,” Collins said. “Although the mice modified with the gene only had 20% of those cells corrected, it looked like a 100% correction: The uncorrected cells were dead, leaving only the healthy cells modified with the base. We have never seen anything like it ”with any other experimental progeria therapy.
CRISPR mice also looked and moved better, in addition to living a median of 510 days compared to 215 days for untreated mice. Children in Eiger BioPharmaceuticals’ recently approved clinical trial of lonafarnib lived an average of 2.5 years, or almost 20%, longer than untreated children.
Fourteen days in mice (the age at which injection of the Basal Editor gave the best results) is comparable to 5 or 6 years in a child. Although more research needs to be done before a clinical trial can be launched – on the one hand, Liu continues to make improvements to the core editor – “we would be very disappointed if this ended up as just one article. Liu said. He is a co-founder of core publishing company Beam Therapeutics, which said in a statement that it “is actively working with research teams and with the Progeria Research Foundation to explore options for advancing technology in the field. basic edition for children living with progeria. . “
Collins is hoping that the usual decades between healing mice and healing people might not apply here. “Progeria is such a heartbreaking disease that it prompts a lot of people to work on it,” he said. And the record pace of Covid-19 vaccine development has made researchers around the world wonder why clinical cure trials can’t go faster: “We’ll see if we can jump over some hurdles,” a- he declared.
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