Scientists are rewriting the code of life with a new technology that promises to cure inherited diseases by precisely correcting genetic typos. Known as base editing, the technology empowers researchers to pick a single letter amongst the three billion that compose the human genome, erase it, and write a new letter in its place.
Base editing is an updated version of the gene editing tool CRISPR, which has revolutionized life sciences research and is making strides in treating genetic blood and liver diseases. But some scientists think base editing, sometimes billed as CRISPR 2.0, could be safer and more precise than the original. And this summer, the sequel technology is being used in patients for the first time.
On Tuesday, Boston biotech Verve Therapeutics announced it had edited the DNA of a person with a genetic condition that causes high cholesterol and predisposes them to heart disease. The base editor is designed to tweak a gene in the liver, curtail the accumulation of cholesterol, and hopefully lower the risk of heart attacks.
Verve chief executive and cofounder Sekar Kathiresan likens the approach to “surgery without a scalpel.” Although the trial is focused on people with the genetic condition familial hypercholesterolemia, Kathiresan hopes the one-and-done therapy may one day be used more broadly, to permanently reduce the risk of heart disease in millions of people with high cholesterol. “We are completely trying to rewrite how this disease is cared for,” he said.
Base editing is making its way into studies for other conditions as well. Earlier this year, researchers at University College London quietly began a clinical trial using base editors to engineer immune cell therapies for leukemia — likely the first time base editors were used as part of any experimental medicine. And Cambridge firm Beam Therapeutics plans to use base editors to treat people with genetic blood diseases in a trial that will launch later this year. The firm also has early stage programs for cancer, liver disease, immune disorders, and vision loss.
The powerful tool that could make all these treatments possible was first conceived by David Liu at the Broad Institute of MIT and Harvard in 2013, when he realized that CRISPR was not a panacea. CRISPR acts like a pair of molecular scissors that cut specific sequences of DNA. While that’s useful for turning problematic genes off, it doesn’t help to fix them.
“We really need ways to correct genes, not just disrupt them,” said Liu. “And that’s where base editing comes in.”
Liu’s base editors are modified versions of CRISPR that act like molecular erasers and pencils, swapping one of the four bases, or letters, of DNA for another. One version, developed by his postdoctoral researcher Alexis Komor in 2016, converts a C into a T. A second base editor, developed by his graduate student Nicole Gaudelli in 2017, changes an A into a G.
These two base editors could correct about 60 percent of all single-letter typos that cause rare genetic diseases, yet that’s not what scientists are doing first. The three clinical trials of the technology starting this year will use base editors to intentionally create typos.
The potential power of that strategy is clear in Verve’s clinical trial. Scientists have discovered multiple genes that raise cholesterol and increase the risk of heart attacks. People with genetic mutations in one of these genes, called PCSK9, have extremely low levels of LDL cholesterol — often called “bad cholesterol” — and are “remarkably protected against heart attack,” Kathiresan said. “Our idea was to develop a gene editing medicine that would mimic the natural situation.”
Verve uses base editors to introduce a mutation in the PCSK9 gene of patients with familial hypercholesterolemia. The results in monkeys have been remarkable, lowering levels of LDL cholesterol by about 70 percent after two weeks. The levels remained low for at least two years, Kathiresan said.
“This seems like a bigger effect than I would have predicted,” said Dr. Sarah de Ferranti, chief of ambulatory cardiology at Boston Children’s Hospital. “Even if it were half as effective, I still think that would be a huge game changer.”
Current drugs available for familial hypercholesterolemia lower LDL cholesterol by as much as 50 to 60 percent, but they must be injected once or twice a month, a schedule many patients have a hard time sticking to, said Dr. Gary Balady, director of preventative cardiology at Boston Medical Center. “Having a one-time treatment has the potential to save lots of lives,” he said.
The first person dosed in Verve’s trial lives in New Zealand, but the company expects regulators to greenlight the trial in the United States and United Kingdom later this year. Gaudelli, who developed the base editor Verve is using, said seeing her invention in the clinic is the “gift of a lifetime.”
Verve’s therapy is an infusion that edits DNA directly in patients. The other two base editor studies starting this year will edit cells in the lab and reinfuse them into patients. Dr. Waseem Qasim, a professor of cell and gene therapy at the UCL Great Ormond Street Institute of Child Health, has already begun a clinical trial in London using base editors to make three changes that will help immune cells fight relapsed T cell leukemia in children.
Qasim previously developed cell therapies for blood cancers using CRISPR, and he was excited to switch to base editing. Cutting multiple genes at once with CRISPR could cause chromosomes to get jumbled up, he said. “Whether there’s any side effects arising from that or not, we don’t know. But there could be.” Since base editors don’t cut DNA, they should be much safer, he said.
Later this year, Beam Therapeutics will use base editors to treat people with sickle cell disease and a related condition called beta thalassemia.
Jennifer Doudna, the University of California Berkeley scientist who co-invented CRISPR in 2012, said that while base editing “works very well in research settings,” and could be fine for disrupting genes, she doesn’t think it currently has the precision needed to correct mutations. Base editors often edit other DNA letters around the single letter that you want to edit, she said. “So that means you end up usually getting more editing than you might want.”
The groups developing base editing therapies say they have scoured the genomes of edited cells in the lab to look for any unwanted editing. John Evans, chief executive of Beam Therapeutics, said these off-target edits are predictable and thus largely avoidable. “You can kind of engineer around it,” he said.
Liu hopes the three clinical trials of base editors this year are just the start of many more to come. “It still sounds to me like science fiction that you can go into a patient and make a precise change in the sequence of their genome at a position that would otherwise destine them to suffer from a grievous genetic disease,” Liu said.
“To be able to take control of our genomes, to me, is one of the most human things we can do.”