Reengineering Life is a column from Future Human about the ways humans are using biology to reprogram our bodies and the world around us.
Children who are born with a rare genetic disease called progeria tragically live, on average, only until their mid-teens, though they look much older. Their bodies age so rapidly — up to 10 times faster than normal — that they usually die prematurely from heart attacks or strokes before they can finish high school. The culprit is a single-letter misspelling in their DNA.
Now, scientists have successfully corrected this misspelling in mice that have the disease by using a new kind of gene editing called base editing, raising hopes that a cure for children with progeria may be possible. The results were published on January 6 in the journal Nature.
“It’s quite a remarkable finding,” Robert Goldman, PhD, a professor of cell and developmental biology at Northwestern University who was not involved in the study, tells Future Human. “They saw a really substantial correction of defects.” Goldman would know — he carried out important early research on the protein progerin with one of the study authors, Francis Collins, MD, PhD, who is now director of the National Institutes of Health.
In November, the U.S. Food and Drug Administration approved the first drug for progeria, called lonafarnib. While it’s been shown to extend the lives of patients by about two and a half years, it’s by no means a cure. Base editing, however, may provide future patients with the chance at living a long, healthy life.
“They saw a really substantial correction of defects.”
DNA is composed of four chemical bases: A, C, G, and T. Most cases of progeria, also known as Hutchinson-Gilford progeria syndrome, are caused by a mutation in the LMNA gene, in which a C is swapped for a T. This tiny error leads to the formation of a toxic protein called progerin, which damages cells and in doing so, accelerates the aging process.
Base editing seemed like the perfect tool to address this problem. Whereas traditional CRISPR gene editing works by cutting DNA’s double helix structure, base editing simply substitutes a single DNA letter for another without damaging the DNA.
While CRISPR editing is making inroads in treating certain genetic disorders, like sickle cell disease, it’s still prone to error. Base editing is more precise. Unlike CRISPR, often described as “genetic scissors,” base editing is designed to work more like the find-and-replace function in a word processor. The approach could be safer than traditional CRISPR, because when DNA repairs itself after a break, the DNA around the edited gene often gets scrambled.
“The ideal therapy would be to reverse that mutation by rewriting the DNA back to what it was supposed to be,” study author Jonathan Brown, MD, a cardiologist at Vanderbilt University Medical Center, tells Future Human. He undertook the research with a team at the Broad Institute of MIT and Harvard that included David Liu, PhD, who pioneered the base editing technique.
In the study, one group of mice received a single injection of the base editor, while a control group was given an injection of saline. By the time the mice were six weeks old, 10% to 60% of cells in their bones, skeletal muscle, liver, heart, and aorta were corrected. And the physical benefits were even more profound: Brown says it was easy to tell just by looking at the mice that the ones treated with base editing were healthier. They had more energy, shinier coats, and more normal posture.
The untreated mice, meanwhile, developed a hunchback and were less mobile. After several months, the physical differences in the two groups became even more profound, Brown says. The untreated mice slowed down significantly and their coats became scruffy.
Ultimately, the gene-editing therapy extended the lifespan of the treated mice. Untreated mice lived to an average of seven months, whereas the treated animals survived to around a year and a half — twice as long. Healthy mice usually live to about two years. Autopsies of the mice showed that the tissues and blood vessels in the treated group looked comparable to those of normal mice of the same age.
“Would I have dreamt that we could do this five years ago? No. The technology is moving so quickly, it’s mind-boggling.”
“These are the most dramatic results that I have seen in progeria mice,” says study co-author Leslie Gordon, MD, PhD, adding that these results give hope to the families of children born with the disease. Gordon is the medical director of the Progeria Research Foundation, which partially funded the study and has been funding research into potential treatments for progeria since its founding in 1999. She and her husband started the nonprofit organization shortly after their son Sam was diagnosed with progeria at 22 months old. He died of the disease in 2014 at age 17.
The foundation helped Brown and his collaborators obtain skin cells from people with progeria for earlier experiments with base editing. In lab experiments, the approach fixed the mutation in 90% of the cells.
Of course, correcting the mutation in skin cells and mice isn’t the same as reversing the disease in people, but the researchers are hopeful that their work will eventually lead to a treatment. Brown says there’s still more work to be done to ensure base editing is safe and effective before testing it in people, but he’s optimistic that human trials could begin in a few years. The study authors are already taking the next steps with the Progeria Research Foundation and Beam Therapeutics, a gene-editing startup co-founded by Liu, to advance the therapy toward clinical trials.
The approach could also have implications for other genetic diseases caused by single-base DNA changes. Goldman says the mutation that causes progeria is just one of dozens in the LMNA gene that are known to cause rare diseases.
In the meantime, gene editing will likely only get better and more precise. “Would I have dreamt that we could do this five years ago? ” Goldman says. “No. The technology is moving so quickly, it’s mind-boggling.”