Of all genetic diseases, progeria syndrome is one of the most heartbreaking. Children born with a single miscoding in the responsible gene will suffer premature aging and typically don’t live past their teens. Hope brightened Wednesday, as scientists reported that a novel gene-editing technology was able to correct the genetic mutation in lab mice and spare them progeria’s effects.
While cautioning that work remains before the treatment is ready for humans, the researchers were optimistic.
“We’re very excited about the implications of this study for a potential one-time treatment that directly corrects the root cause of the disease instead of treating its symptoms,” says David Liu, a Harvard University chemistry professor and genomics researcher at the Broad Institute, who led the project along with Vanderbilt University cardiology professor Jonathan Brown and the director of the National Institutes of Health, Francis Collins.
Reporting in the journal Nature, the scientists say that a single injection corrected the progeria mutation in 20% to 60% of the cells of mice born with the condition—reducing levels of a toxic protein that rapidly ages those with the disease and causes a child to die from heart disease at an average age of 14. Treated mice lived nearly a normal lifespan, and more than twice as long as untreated animals with the mutation.
“It’s fantastic,” says Leslie Gordon, a co-author of the study and a pediatrics professor at Brown University, whose son Sam Berns died from progeria in 2014. “Of course, it can never come fast enough for me or any of the families that love these children so very much…but we are moving forward.”
The treatment is made possible by a new way of fixing faulty genes, known as base-editing, that emerged in 2016 from Liu’s lab. Base-editing is being commercialized by
(ticker: BEAM), which plans a clinical trial this year in sickle-cell anemia. Excitement over the technology has lifted Beam stock fourfold since its debut in February 2020, to a recent price of $84.
Base-editing is a variant of the gene-manipulation breakthrough called Crispr-Cas editing whose discovery won the chemistry Nobel Prize in October for the scientists Jennifer Doudna and Emmanuelle Charpentier. The ability of Crispr-Cas molecules to target and disrupt troublesome genes is being developed by companies like
While Crispr-Cas can knock out an instruction coded in our cells’ genes, base-editing can correct a single miswritten “letter” in a gene’s instructions. That suits it for treating about 30% of genetic disorders, notes Liu, including many that can’t be addressed by Crispr-Cas editing or the first generation of gene therapies—which insert genes that augment a cell’s flawed inheritance.
One hard-to-treat mutation causes Hutchinson-Gilford progeria syndrome, as the disease is known to doctors. If the single-letter mutation appears in one of the two inherited copies of the gene that codes for a cell-structure protein, then toxic versions of the protein destabilize cells throughout the body, including those in bones, fat, skin and—with fatal consequences—the arteries.
Gene-augmentation therapy couldn’t help. Adding a correct copy of the gene might spur production of healthy proteins, but the mutant gene would keep producing the toxic form. Crispr-Cas therapy might knock out the troublesome gene, but it would probably also knock out any healthy copies of the gene that a patient might have—or it might make the mutant gene worse. Base-editing held out the promise of correcting the mutation’s single errant letter and restoring the gene’s healthy function.
Liu says he visited the NIH in 2018 to lecture on his gene-editing work. In a chat with NIH director Collins before the talk, Liu mentioned that his lab had some encouraging early data on base-editing the progeria mutation. Collins had long studied progeria for insights on the genetics of aging, so he urged Liu to include those new data in the lecture. Liu recalls adding the slides in the rest room, just before the talk.
Afterward, Collins proposed that their labs join forces to test the base editor on a population of mice that the NIH had modified to carry the progeria mutation. Those mice became the subjects for the studies reported Wednesday.
Base-editing worked even better than the scientists had expected. While the one-shot treatment corrected the DNA in just a third of the heart cells of the mice, it resulted in a 90% decrease in cell levels of toxic protein and restored heart tissue to normal appearance.
“It’s one of the pleasantly surprising mysteries of how strong the rescue was,” says Liu. “It was that moment we realized something really special was happening here.”
The promising news of the base-editing study comes barely a month after the U.S. Food and Drug Administration approved the first medicine that addresses progeria. Following 13 years of research,
(EIGR) got clearance on Nov. 25 to market Zokinvy, which it developed with support from the Progeria Research Foundation—a group started by Leslie Gordon and her family after her son Sam was diagnosed.
Advocacy groups like the Progeria foundation have been crucial to the discovery of rare disease treatments, since they can muster up patients willing to participate in clinical trials. There are only a few hundred children worldwide with Progeria syndrome, and only a human trial will determine if base-editing does more than just help mice.
“I think of this study as a sentinel,” says Gordon. “If we can really make a difference in the lives of children with progeria, then perhaps we can reverse other significant mutations, too.”
Write to Bill Alpert at [email protected]