A 4-year-old child with progeria, a syndrome with features of premature aging arising from a mutated gene
MARTIN ZABALA Xinhua / eyevin / Redux
By Jocelyn Kaiser
One mouse is hunched over, gray and moves barely 7 months old. Others wore smooth black coats at 11 months and ran around. The videos and other results of a new study have inspired hope in treating children born with progeria, a rare, deadly, genetic disease that causes symptoms such as premature aging. In mice with a mutation that causes progeria, a cousin of the celebrated genome editor, known as CRISPR, corrected the DNA defect and prevented the heart damage that is typical of the disease, a research team reported today in Earth. Treated mice lived for about 500 days, more than twice as long as untreated animals.
“The outcome is incredible,” said gene therapy researcher Guangping Gao of the University of Massachusetts, who was not involved in the study.
Although the developers of progeria therapy are aiming to improve it, they are also taking steps to test the current version in children affected, and some other scientists endorse a rush. The mouse’s results exceed ‘nobody’s wildest expectations’, says Fyodor Urnov, a researcher in gene editing at the University of California, Berkeley. “The new data is essential to treat a child with progeria … and will do so in the next three years.”
It is estimated that about 400 people in the world have Hutchinson-Gilford progeria syndrome, which is the result of a single base change in the gene for a protein called lamin A that helps to form the membrane that forms the nucleus in cells. . The resulting abnormal protein, called progerin, disrupts the nuclear membrane and is toxic to cells in many tissues. Toddlers quickly become bald and have growths, loss of body fat, stiff joints, wrinkled skin, osteoporosis and atherosclerosis. People with progeria die on average of about 14 years from a heart attack or stroke.
Researchers have previously used CRISPR to disrupt the activity of the mutated gene for lamin A in progeria mice. But their health has only modestly improved and disabling a person’s good copy of the gene can cause harm. So David Liu of Harvard University and the Broad Institute moved on to basic machining, a DNA-modifying method that was originally inspired by CRISPR and developed in his laboratory. Unlike CRISPR, which makes duplicate sections in DNA, the base editor used in the progeria study forms only one strand and exchanges a single base. Basic editors treated liver, eye, ear, blood, and brain disorders in mice, and Liu wanted to try a “notorious and devastating” disease with multiple organs or tissues.
Liu’s group works with cardiologist Jonathan Brown of Vanderbilt University 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 basic tillage approach in cultured cells from two. progeria patients, and found that it corrected the mutation while making few undesirable changes elsewhere in the genome. They then package DNA that the base editor encodes into adeno-associated viruses (AAVs), a standard delivery agent for gene therapies, and inject it into young mice with the progeria mutation.
“The results were much better than we dared,” Collins says. When the mice were examined six months later, between 20% and 60% of their bone, skeletal muscle, liver, heart and aorta carried the DNA solution. Progerine levels dropped and laminin A levels rose in several tissues. Although the mice were 2 weeks old at the time of treatment, or about 5 years old in human years, their aortas months later had virtually no signs of fibrous tissue growth or loss of smooth muscle cells seen in mice and children with progeria. . “It harnesses the potential of this technology,” said Charles Gersbach, Duke University’s gene editing researcher.
Some rodents eventually develop liver tumors, a problem previously seen in mice receiving high doses of AAV gene therapy. It has been shown that no people 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 evaluate more effective base editors for that.
Study co-author Leslie Gordon, a Brown University doctor whose son died of progeria and who founded the Progeria Research Foundation, does not want to wait for ‘next iteration’ before developing plans and raising money for treatment. in children. . Her foundation is talking to companies, including Beam Therapeutics, which co-founded Liu, in hopes of launching a clinical trial. “We’ll find a way to do that for these kids,” Gordon says.