A More Elegant Form of Gene Editing Advances To Human Testing

in April 2016 Waseem Qasim, professor of cell and gene therapy, was captivated by a new scientific paper describing a revolutionary way to manipulate DNA: basic editing. The paper, published by David Liu’s lab at the Broad Institute of MIT and Harvard, describes a version of Crispr gene editing that allows 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 consists of a sequence of four chemical bases: A, C, G, and T. These combine to form the double helix structure of DNA. Traditional Crispr and previous gene editing methods work by cutting the double helix of DNA, for example, to eliminate a disease-causing gene. Base editing, on the other hand, simply replaces one chemical base with another to correct a mutation or disable a gene. The first basic regulator described by Liu’s lab could convert a C to a T. Others have been invented since then.

Scientists immediately recognized the value of basic regulation. Many inherited diseases, such as cystic fibrosis and sickle cell anemia, are caused by single base changes in DNA. Now these mutations can in theory be corrected by converting one base to another. Qasim and his team wanted to use basic editing for another purpose: replacing immune cells in an attempt to cure cancer.

Using Liu’s paper as a guide, Qasim and his team created their own key regulator and found it incredibly efficient at making genetic changes to cells in the lab. For the next six years, they worked to improve the technology, and in May put the technology to the final test, using it to treat a leukemia patient in hopes of curing the cancer. This new form of gene editing has been used for the first time to treat a human.

A 13-year-old patient, named Alyssa, was diagnosed with a rare and aggressive type of cancer called T-cell leukemia in May 2021. T cells, an important part of the immune system, 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 experimental baseline modulation therapy. Qasim and his team collected T cells from a healthy donor and used base editing to make four distinct changes (all C to T base conversions) in the cells. The edits allowed the donor T cells to bypass the body’s defenses, recognize a particular receptor on the leukemia cells, and kill the cancer. Doctors at the Great Ormond Street Institute of Child Health, part of University College London, then grafted 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 in cancer immunotherapy. Qasim says it can be life-threatening in some patients, but Alyssa’s symptoms are mild and heal quickly. One month after her infusion, her cancer had regressed and she remains well. “We have confirmed that disease levels are still undetectable,” says Qasim. 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.)

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