One mouse is hunched over, graying, and barely moves at 7 months old. Others, at 11 months, have sleek black coats and run around. The videos and other results from a new study have inspired hope for treating children born with progeria, a rare, fatal, genetic disease that causes symptoms much like early aging. In mice with a progeria-causing mutation, a cousin of the celebrated genome editor known as CRISPR corrected the DNA mistake, preventing the heart damage typical of the disease, a research team reports today in Nature. Treated mice lived about 500 days, more than twice as long as untreated animals.
“The outcome is incredible,” says gene-therapy researcher Guangping Gao of the University of Massachusetts, who was not involved with the study.
Although the developers of the progeria therapy aim to improve it, they are also taking steps toward testing the current version in affected children, and some other scientists endorse a rush. The mouse results are “beyond anyone’s wildest expectations,” says Fyodor Urnov, a gene-editing researcher at the University of California, Berkeley. “The new data are an imperative to treat a child with progeria … and do so in the next 3 years.”
About 400 people in the world are estimated to have Hutchinson-Gilford progeria syndrome, which results from a single-base change in the gene for a protein called lamin A that helps support the membrane forming the nucleus in cells. The resulting abnormal protein, called progerin, disrupts the nuclear membrane and is toxic to cells in many tissues. Toddlers soon become bald and have stunted growth, body fat loss, stiff joints, wrinkled skin, osteoporosis, and atherosclerosis. People with progeria die on average around age 14 from a heart attack or stroke.
Researchers have previously used CRISPR to disrupt activity of the mutated gene for lamin A in progeria mice. But their health improved only modestly, and disabling a person’s good copy of the gene could cause harm. So David Liu of Harvard University and the Broad Institute turned to base editing, a DNA-changing method originally inspired by CRISPR and developed in his lab. Unlike CRISPR, which makes double-strand cuts in DNA, the base editor used in the progeria study nicks just one strand and swaps out a single base. Base editors have treated liver, eye, ear, blood, and brain disorders in mice, and Liu wanted to try one on an “infamous and devastating” disease that involves multiple organs or tissues.
Liu’s group teamed up with Vanderbilt University cardiologist Jonathan Brown and Francis Collins, director of the National Institutes of Health, whose group was one of two that identified the progeria mutation in 2003. The team first tested the base-editing approach in cultured cells from two progeria patients, finding that it corrected the mutation while making few unwanted changes elsewhere in the genome. They then packaged DNA encoding the base editor into adeno-associated viruses (AAVs), a standard delivery vehicle for gene therapies, and injected these into young mice with the progeria mutation.
“The results were far better than we had dared to hope,” Collins says. When the mice were examined 6 months later, between 20% and 60% of their bone, skeletal muscle, liver, heart, and aorta carried the DNA fix. Progerin levels fell and lamin A levels rose in several tissues. Even though the mice were already 2 weeks old when treated, or about age 5 in human years, their aortas months later bore virtually no signs of the fibrous tissue growth or loss of smooth muscle cells seen in mice and children with progeria. “It hits home the potential of this technology,” says gene-editing researcher Charles Gersbach of Duke University.
Some of the rodents eventually developed liver tumors, a problem seen before in mice receiving high-dose AAV gene therapy. No people have been shown to have developed liver tumors as a result of such treatments. Still, lowering the AAV dose to improve safety “is a goal,” Liu says. He and Collins are evaluating more efficient base editors to that end.
Study co-author Leslie Gordon, a Brown University physician whose son died from progeria and who co-founded the Progeria Research Foundation, doesn’t want to wait for “the next iteration” before developing plans and raising money to test the treatment in children. Her foundation is talking to companies, including Beam Therapeutics, which Liu co-founded, in hopes of launching a clinical trial. “We will find a way to get this done for these kids,” Gordon says.