Sharon Lees/ Great Ormond Street Hospital


November 5, 2015

Layla received gene-edited immune cells from a healthy donor.

Layla, a one-year-old girl with leukaemia, is in remission thanks to gene-editing technology that allowed her to receive modified immune cells from another person.

Her case represents the second trial of gene-editing as a therapy — the first was carried out last year in patients with HIV. More similar trials are planned — and companies are also preparing to trial therapies that inject DNA that codes for gene-editing enzymes directly into the human body.

Immunologist Waseem Qasim of Great Ormond Street Hospital for Children NHS Trust in London, whose team treated the girl, says that his team had planned to start a safety trial next year in 10–12 patients. But when the researchers came across the baby, in whom all other treatments had failed, they were able to obtain special permission to treat her with the new technology. Several months after the procedure, Qasim says that she is doing well. His team will present the case  in December at an American Society of Hematology meeting in Orlando, Florida.

To administer the therapy, the researchers extract immune cells called T-cells from a healthy donor, and expose them to a type of DNA-cutting enzyme called a TALEN. The enzyme deactivates immune genes that would otherwise cause the donor cells to attack when injected into a person with leukaemia, and modifies genes to protect the new cells from anti-cancer drugs that the patient is taking.

The individual then undergoes therapy to destroy his or her own immune system, which is replaced with the modified cells. The treatment is not a permanent solution for leukemia patients, says Qasim, but rather a ’bridge‘ to keep the person alive until a matched T cell donor can be found.

The first ever use of gene-editing in people employed a similar ex-vivo approach. Last year, Sangamo BioSciences in Richmond, California, published results1 from a clinical trial in which it used gene-edited cells to treat 12 people with HIV. Instead of TALENs, the researchers used a different class of DNA-cutting enzyme called a zinc-finger nuclease (ZFN). When added to blood extracted from the patients, the ZFNs cut the gene for a protein on T-cells targeted by HIV, and the team then pumped the cells back into the patients. The results were positive — at the time of the announcement, half of the participants were cleared to stop taking their anti-retroviral drugs —  and Sangamo tells Nature that it has now treated more than 70 patients with the therapy.

Haemophilia hope

For some diseases, however, it makes more sense to edit the genome in vivo — for example, if the target cells are in an organ or tissue type harder to remove than blood.

In a study presented in October at a meeting of the US National Academies of Sciences, Engineering and Medicine in Washington DC, Sangamo senior scientist Fyodor Urnov reported that his group had injected 15 monkeys with viruses that carried genes encoding ZFN and normal versions of factor IX — a blood-clotting protein produced by the liver, which is mutated in people with haemophilia B.

The ZFN cut the genome at a section that encodes a protein called albumin, which is made in large quantities in the liver, and inserted a healthy version of the factor-IX gene. The team found that the monkey’s livers began producing much more factor IX: the protein’s levels in the blood increased by 10%. Urnov says that the site could be a good place to insert other genes2, and likens the albumin gene to “a USB port in the human genome”.

A committee at the US National Institutes of Health, which approves all clinical trials involving modified DNA, gave the green light to human trials of the factor-IX therapy in September, according to Urnov, but Sangamo must still get permission from the US Food and Drug Administration (FDA). Urnov says that the company will apply by the end of the year and, if successful, that trials could begin at the beginning of 2016. Sangamo also plans to apply for permission to do several other in vivo gene-editing trials, including of therapies for the blood diseases haemoglobinopathy and beta thalassemia.

Growing concerns

Both ex-vivo and in-vivo therapies could cause cuts and mutations elsewhere in the genome, but the in-vivo variety introduces another concern because the DNA-delivering vector can remain active in the body for years after injection. Biologist Valder Arruda of the University of Pennsylvania in Philadelphia, who is exploring factor-IX gene-therapy approaches for haemophilia, worries that this could have unforeseen effects. Sangamo, however, says that it has not seen evidence of such destructive effects in its animal studies.

Other challenges of editing in vivo, says Qasim, include ensuring that enough of the target cells actually get edited and that the vector delivers its payload to the right part of the body.

Meanwhile, the list of disorders that editing in vivo could help to treat is growing. In a study presented at a synthetic-biology meeting in April, biomedical engineer Charles Gersbach at Duke University in Durham, North Carolina, reported injecting a vrial vector that coded for a DNA-cutting enzyme into the muscles of mice with the mutation responsible for muscular dystrophy, a muscle-wasting disease. The injections corrected the gene in about 20% of muscle cells — enough to substantially improve their muscle tone and strength. “I think [in vivo] is the next wave of gene editing,” he says.