Biologists tend not to discuss 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 plans to present such findings, which he’d peeked at over his graduate student’s shoulder, when he gave a high-profile talk in 2018 at the National Institutes of Health on a form of the CRISPR genome-editing system that he’d invented.
Not that he wasn’t tempted. Student Luke Koblan had used the clever new form of CRISPR, called base editing, to alter a single misspelled pair of “letters” among the 3 billion in the DNA of cells taken from children with progeria, an infamous and fatal genetic disease marked by accelerated aging. Koblan had done this work in lab dishes, and had also corrected the progeria mutation in a mouse carrying the human gene that, as a result, aged so quickly that by toddlerhood, it was like a picture of Dorian Gray with whiskers.
Chatting before his talk with NIH Director Francis Collins, who discovered the progeria mutation in 2003, Liu happened to mention the results. Collins was blown away. You have to put that 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 talk with how a CRISPR base editor might just be the long-sought cure to progeria. Not a treatment, like the drug lonafarnib that was approved this past November, but a one-and-done cure.
Liu’s talk led to a collaboration with Collins, the CRISPR base-editing of 62 mice with progeria, and, on Wednesday, the announcement that the study produced “results so much better than anything we ever tried,” Collins said. The base editor was so good at repairing the mice’s progeria that half the animals lived 510 days — old age for mice, and twice as long as untreated mice.
With such stunning results, “this could become a therapy for [progeria] and perhaps other rare accelerated-aging syndromes,” said Wilbert Vermeij of the Oncode Institute in the Netherlands, an expert on the biology of aging who was not involved in the study.
If the mouse results are confirmed in human trials, “this has the feel of something that could be a true genetic cure with a single injection,” not a drug children have to take all their lives, 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 worldwide. Although they seem healthy as babies, by age 1 or 2 they are failing to grow, losing the fat under their skin, and developing vascular and other problems characteristic of 80-year-olds. They typically die around age 14 of stroke, cardiovascular disease, and other illnesses of old age. Cognitively normal, they know exactly what is happening to them.
The cause of progeria is a single T-A base pair in the DNA where a C-G should be. The resulting mutant protein, called progerin, is poisonous to cells.
Base editors are made for such a mutation: They convert one DNA letter into a different one, in this case the mutant T-A to the healthy C-G. And they do so without chopping up the double helix, as standard CRISPR does, which risks mangling genes.
The scientists first slipped a T-to-C base editor into 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 we were getting such significant correction at a disease-causing site,” Liu said. The cells began producing healthy protein, called lamin A, and very little poisonous progerin, they reported in Nature.
Cells in lab dishes are all well and good, but Liu knew he had to test the system on mice — way more of them than the lone animal in Koblan’s initial experiment. Collins had been so excited about the preliminary results that he invited Liu to collaborate — an offer not to be refused, since NIH has the world’s largest colony of progeria mice.
The pandemic slowed things down — Collins had to send home all his lab workers from March to July, until they figured out shifts and safe practices — but soon dozens of 3- and 14-day-old progeria mice were being 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 base editor to reach as many types of tissue as possible.)
After six weeks, 10% to 60% of cells in different organs, from the aorta to liver, heart, muscle, and bone, had been successfully edited. But those numbers lowballed the improvement. The smooth muscle cells inside blood vessels “are usually a graveyard at six months,” Collins said. “Although the gene-edited mice had only about 20% of these cells corrected, it looked like 100% correction: The uncorrected cells had died, leaving only the healthy, base-edited cells. We’ve never seen anything like it” with any other experimental progeria therapy.
The CRISPR’d mice also looked better and moved better, in addition to living a median of 510 days vs. 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 injecting the base editor had the best results) is comparable to 5 or 6 years in a child. Although more research needs to be done before a clinical trial could be launched — for one thing, Liu is still making improvements to the base editor — “we would be very disappointed if this ended up as just a paper,” Liu said. He is a co-founder of the base-editing company Beam Therapeutics, which said in a statement that it “is actively working with the research teams and with the Progeria Research Foundation to explore options for moving base editing technology forward for children living with progeria.”
Collins is hopeful that the usual decades between curing mice and curing people might not apply here. “Progeria is such a heartbreaking disease, it draws a lot of people to work on it,” he said. And the record-setting pace of Covid-19 vaccine development has made researchers everywhere question why clinical trials for cures can’t go faster: “We’ll see if we can jump over some hoops,” he said.