Biologists tend not to discuss experimental results on a handful of cells and a single solitary mouse – too preliminary, too sketchy. So David Liu of the Broad Institute did not intend to present such findings, which he looked over the shoulder of his graduate student, when he gave a sensational speech at the National Institutes of Health in 2018 on a form of the CRISPR genome. care system he invented.
Not that he was not tempted. Student Luke Koblan used the clever new form of CRISPR, called basic processing, to change a single misspelled pair of “letters” under the 3 billion in the DNA of cells taken from children with progeria, a notorious and deadly genetic disease characterized by accelerated aging. Koblan did this work in laboratory dishes, and also corrected the progeria mutation in a mouse carrying the human gene, which consequently aged so fast that it was by toddlers like a photo of Dorian Gray with mustache.
Prior to the conversation with NIH Director Francis Collins, who discovered the progeria mutation in 2003, Liu happened to mention the results. Collins was blown away. You need to put it in your talk, Collins said. When the head of the NIH speaks, biologists listen – and in Liu’s case, run to the men’s room to update his speech on how a CRISPR base editor might just be the long-term remedy for progeria. Not a treatment like the drug lonafarnib that was approved last November, but a one-of-a-kind drug.
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Liu’s speech led to a collaboration with Collins, the CRISPR basic care of 62 mice with progeria, and Wednesday’s announcement that the study “yields results so much better than anything we’ve ever tried,” Collins said. The base editor was so good at restoring the mice’s progeria that half of the animals lived 510 days – age for mice and twice as long as untreated mice.
With such beautiful results, ‘it could become a therapy for [progeria] and perhaps other rare syndromes with accelerated aging, ”says 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 mouse results are confirmed in human trials, ‘it has the feel of something that could be a true genetic drug with a single injection’, no drug children need to take their whole lives, says 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 the age of 17).
There are only about 200 children with progeria worldwide. Although they look healthy as babies, they do not grow at the age of 1 or 2, they lose fat under their skin and they develop vascular and other problems that are characteristic of 80-year-olds. 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 the DNA where a CG should be. The resulting mutant protein, called progerin, is toxic to cells.
Base editors are designed for such a mutation: they convert one DNA letter into another, in this case the mutant TA to the healthy CG. And they do so without chopping up the double helix, as standard CRISPR does, which threatens the risk of gene confusion.
The scientists first donated a T-to-C base editor in cells donated by children with progeria, using a lentivirus to carry the genome editor into the cells; 90% of the cells had their DNA corrected. “We were really surprised that we were getting such significant corrections in a disease-causing field,” Liu said. The cells began to produce healthy proteins, called lamin A, and very little toxic progerin, they report in Nature.
Cells in laboratory dishes are fine, but Liu knew he had to test the system on mice – much more than the single animal in Koblan’s first experiment. Collins was so excited about the preliminary results that he invited Liu to work together – an offer that should not be denied, as NIH has the largest colony of progeria mice in the world.
The pandemic has slowed things down – Collins had to send all his lab workers home from March to July, until they realized shifts and safe practices – but dozens of 3- and 14-day-old progeria mice will soon be injected with the base editor. via an adeno-associated virus near the eye or in the abdominal cavity. (Both sites are connected to the circulatory system, and the scientists wanted the editor-in-chief 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 liver, heart, muscles and bone, were successfully processed. But the numbers have slowed the improvement. The smooth muscle cells in blood vessels are usually a cemetery at six months, Collins said. ‘Although only about 20% of the cells were corrected by the uncared-for mice, this seemed like a 100% correction: the uncorrected cells died, leaving only the healthy, basic-corrected cells. We have never seen anything like it ”with any other experimental progeria therapy.
The CRISPR mice also looked better and moved better, except that they lived a median of 510 days versus 215 days for untreated mice. Children in the clinical trial of the recently approved lonafarnib, from Eiger BioPharmaceuticals, lived an average of 2.5 years, or almost 20%, longer than untreated children.
Fourteen days in mice (the age when the base editor was injected 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, Liu is still making improvements to the base editor – “we would be very disappointed if it’s just an article,” Liu said. He is a co-founder of the basic care company Beam Therapeutics, which said in a statement that he “works with the research teams and with the Progeria Research Foundation to explore options to promote basic editing technology for children living with progeria.”
Collins is hopeful that the usual decades between the healing of mice and the healing of humans will not apply here. “Progeria is such a heartbreaking disease, it attracts a lot of people to work on it,” he said. And the record pace of Covid-19 vaccine development has left researchers everywhere doubting why clinical trials for cure could not go faster: “We’ll see if we can jump over a few rings,” he said.