‘Incredible’ gene-editing result in mice inspires plans to treat premature-aging syndrome in children

About 400 people in the world are estimated to have Hutchinson-Gilford progeria syndrome - 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 progerin disrupts the nuclear membrane and is toxic to many cells. Toddlers soon become bald and have stunted growth, body fat loss, stiff joints, wrinkled skin, osteoporosis, and atherosclerosis. People with progeria die around the age 14 from a heart attack or stroke.

Researchers have 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. 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 disorders in individual organs in mice, and Liu wanted to try one on an disease that involves multiple organs or tissues.

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.

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, 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.

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.