A 4 year old child with progeria, a syndrome with characteristics of premature aging that results from a mutated gene
MARTIN ZABALA Xinhua / eyevin / Redux
By Jocelyn Kaiser
A mouse is hunched, aging and barely moving at 7 months of age. Others, aged 11 months, wear elegant black coats and run around. The videos and other results of a new study inspired hope in the treatment of children born with progeria, a rare and fatal genetic disease that causes symptoms similar to premature aging. In mice with a progeria-causing mutation, a cousin of the famous genome editor known as CRISPR corrected the DNA error, avoiding the heart damage typical of the disease, reports a research team today Nature. The treated rats lived for about 500 days, more than twice that of the untreated animals.
“The result is incredible,” says gene therapy researcher Guangping Gao, from the University of Massachusetts, who was not involved in the study.
While developers of progeria therapy aim to improve it, they are also taking steps to test the current version on affected children, and some other scientists endorse a race. The results of the mice are “beyond wildest expectations,” says Fyodor Urnov, a gene editing researcher at the University of California, Berkeley. “The new data is critical for treating a child with progeria … and doing so in the next 3 years.”
It is estimated that around 400 people worldwide have Hutchinson-Gilford progeria syndrome, which results from a unique change in the gene for a protein called lamina A, which helps to support the membrane that forms the nucleus of cells. The resulting abnormal protein, called progerin, breaks through the nuclear membrane and is toxic to cells in many tissues. Children soon go bald and show stunted growth, loss of body fat, stiff joints, wrinkled skin, osteoporosis and atherosclerosis. People with progeria die on average around the age of 14 from a heart attack or stroke.
The researchers have already used CRISPR to disrupt the activity of the mutated lamina A gene in mice with progeria. But his health improved only modestly, and disabling a person’s good copy of the gene can cause harm. So David Liu, from Harvard University and the Broad Institute, turned to the grassroots edition, a method of changing DNA originally inspired by CRISPR and developed in his laboratory. Unlike CRISPR, which makes double-stranded DNA cuts, the base editor used in the study of progeria cuts only one strand and changes a single base. Base editors treated liver, eye, ear, blood and brain diseases in mice, and Liu wanted to experience one in an “infamous and devastating” disease involving multiple organs or tissues.
Liu’s group joined 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 editing approach based on cultured cells from two patients with progeria, finding that it corrected the mutation while making few unwanted changes in other parts of the genome. They then packaged the DNA encoding the basic editor into adeno-associated viruses (AAVs), a standard delivery vehicle for gene therapies, and injected them into young mice with the progeria mutation.
“The results were much better than we dared to expect,” says Collins. When the mice were examined 6 months later, between 20% and 60% of their bones, skeletal muscles, liver, heart and aorta carried DNA. Progerin levels dropped and lamina A levels increased in various tissues. Although the mice were already 2 weeks old when treated, or about 5 years in humans, their aortas months later showed virtually no signs of fibrous tissue growth or loss of smooth muscle cells seen in mice and children with progeria. “It shows the potential of this technology,” says gene editing researcher Charles Gersbach of Duke University.
Some of the rodents developed liver tumors, a problem seen before in mice that received high-dose AAV gene therapy. No individual has been shown to develop liver tumors as a result of such treatments. Still, reducing the dose of AAV to improve safety “is a goal,” says Liu. He and Collins are evaluating grassroots editors more efficient for this purpose.
Leslie Gordon, co-author of the study, a physician at Brown University whose son died of a progeria and co-founder of the Progeria Research Foundation, does not want to wait for the “next iteration” before developing plans and raising money to test the treatment on children. His 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 do this for these children,” says Gordon.