A More Elegant Form of Gene Editing Progresses to Human Testing

Instead of cutting out chunks of the genome to disable malfunctioning genes, base editing makes a smaller, more precise swap.

In April 2016, Waseem Qasim, a professor of cell and gene therapy, was captivated by a new scientific paper that described a revolutionary way to manipulate DNA: base editing. The paper, published by David Liu’s lab at the Broad Institute of MIT and Harvard, described a version of Crispr gene editing that allowed for more precise changes than ever before. “It seemed like science fiction had arrived,” says Qasim, who teaches at University College London.

The genetic code of every living thing is made up of a string composed of four chemical bases: A, C, G, and T. These pair up to form the double helix structure of DNA. Traditional Crispr and previous gene editing methods work by cutting DNA’s double-stranded helix in order to knock out a disease-causing gene, for instance. Base editing, on the other hand, simply swaps one chemical base for another in order to correct a mutation or disable a gene. The first base editor that Liu’s lab described could convert a C to a T. Others have been invented since. 

Scientists immediately recognized the value of base editing. Many inherited diseases, such as cystic fibrosis and sickle cell anemia, are caused by single-base changes in DNA. Now those mutations could, in theory, be fixed by converting one base for another. Qasim and his team wanted to use base editing for another purpose: altering immune cells in an attempt to treat cancer.

Using Liu’s paper as a guide, Qasim and his team created their own base editors and found that they were incredibly efficient at making genetic changes to cells in the lab. Over the next six years, they worked to improve the technology, and in May, they put it to the ultimate test, using it to treat a leukemia patient in hopes of curing her cancer. It was the first time this new form of gene editing was used to treat a human being.

The patient, a 13-year-old named Alyssa, was diagnosed with a rare and aggressive type of cancer called T-cell leukemia in May 2021. An important part of the immune system, T cells normally protect the body from infection. But in T-cell leukemia, they grow uncontrollably. Doctors tried to treat Alyssa with chemotherapy and a bone marrow transplant, but her cancer came back.

With no other treatment options left, Alyssa was eligible for a trial testing the experimental base editing therapy. Qasim and his team collected T cells from a healthy donor and used base editing to make four separate changes—all C to T base conversions—to the cells. The edits allowed the donor T cells to slip past the body’s defenses, recognize a certain receptor on leukemia cells, and kill the cancer. Doctors at Great Ormond Street Institute of Child Health, part of University College London, then infused the edited cells into Alyssa’s bloodstream. 

After receiving the edited cells, Alyssa experienced an inflammatory side effect known as cytokine release syndrome, a common side effect with cancer immunotherapy. In some patients, it can be life-threatening, but Alyssa’s symptoms were mild and she recovered quickly, Qasim says. A month after her infusion, her cancer was in remission, and she continues to do well. “We’ve confirmed the disease levels are still undetectable,” Qasim says. He presented these preliminary results earlier this month at the American Society of Hematology meeting in New Orleans. (The findings have not yet been published in a peer-reviewed journal.) 

It’s early days for base editing, so researchers will need to treat more patients and follow them for much longer to know whether the treatment is long-lasting. Qasim’s team plans to treat up to 10 children in the trial and monitor them for a year as part of the study, and then to continue with regular checkups.

Qasim and other scientists think base editing may be safer than Crispr since it doesn’t cause breaks in the DNA—a well-known drawback. Crispr works by slicing out problematic chunks of DNA, but it often cuts more than necessary. The cell naturally repairs the damaged area, but the fix is not always seamless. Sometimes, the repair process causes random rearrangements of DNA around the edited site—and in the case of multiple edits, there’s more risk of these rearrangements. While rare, these mistakes could theoretically give rise to cancer. Base editing, on the other hand, doesn’t cause this kind of cellular damage. 

This potential advantage has led US biotech companies Beam Therapeutics and Verve Therapeutics—both of Cambridge, Massachusetts—to pursue base editing treatments for cancer and a handful of inherited diseases. This summer, Verve began a human clinical trial in New Zealand, and both companies are ready to begin trials in the US. “If you want to knock something out, Crispr is a pretty good way to do it. But if you want to fix something, it’s a lot more difficult,” says John Evans, CEO of Beam Therapeutics. “Base editing is this next-generation style of editing that allows us more precise control of the change we want to make.”  

Sekar Kathiresan, CEO of Verve Therapeutics, says the company chose base editing over classic Crispr after comparing the two approaches in mice, monkeys, and human cells in the lab. In a 2021 paper in Nature, scientists at Verve and the University of Pennsylvania found that in monkeys, base editing was able to disable a gene called PCSK9 in the liver, shutting down the production of low-density lipoprotein, or LDL. High levels of LDL, also known as “bad” cholesterol, raise the risk of heart disease and stroke. An infusion of the base-editing lowered the PCSK9 protein by 90 percent and LDL levels by 60 percent. The effect lasted throughout the 10-month study—as well as over the two and a half years the company has followed the monkey since then, Kathiresan says.

Kathiresan sees a future in which base editing becomes a routine treatment for people at risk of repeated heart attacks. In the US, about one in five people who have a first heart attack are readmitted to a hospital for a second one within five years. After a heart attack, it’s common for people to get a stent—a small mesh tube that props open an artery—to improve blood flow. Kathiresan imagines that they might one day receive a second preventative procedure: a one-time base-editing treatment to permanently lower their LDL levels.

For now, the company is focusing on testing the treatment in patients with a genetic form of high cholesterol. In July, a patient in New Zealand became the first person to receive the treatment, which is delivered as a one-time infusion. The company is enrolling more patients in that trial and has yet to announce results. 

Trials in the United States may take more time, because the US Food and Drug Administration (FDA) is closely querying base editing applications. Verve has applied to bring a version of its cholesterol study to the US, but that is currently on hold until the company can provide more safety data to the agency. In a filing with the US Securities and Exchange Commission, Verve said the FDA has asked for more information on the risk of accidental edits to cells other than those in the liver—in particular, eggs and sperm. If these are accidentally edited, the genetic change could be passed on to future generations. 

“We’re not intending to do that,” Kathiresan says. “Our goal is to have the edit happen in that person and affect the cholesterol of the person that we’re treating.” Kathiresan says the company has animal data showing that editing did not occur in sperm or eggs in mice and monkeys.

Meanwhile, Beam Therapeutics has gotten a green light from the FDA to go ahead with a trial testing base editing in patients with sickle cell anemia, an inherited blood disorder that causes severe pain. People with the disease have sticky, misshapen red blood cells because they have abnormal hemoglobin, the protein that carries oxygen through the body. Beam’s treatment makes an A to G edit to activate a fetal version of hemoglobin that counteracts the effects of the sickle cell mutation. Beam is screening potential trial candidates and plans to begin dosing patients next year.

But the company also faced questions and a temporary hold from the FDA when it proposed a second trial, this one for a leukemia treatment that uses base-edited T cells. In an August financial statement, the company disclosed that the FDA wanted more data about potential off-target edits. The agency lifted the hold on Beam’s trial earlier this month, allowing the trial to move forward.

Evans is not surprised with the FDA’s caution. “This is new science and we have patients in mind,” he says. But once trials get underway, 2023 could be the year that base editing joins Crispr at the avant-garde of gene editing.

A More Elegant Form of Gene Editing Progresses to Human Testing

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