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Gene therapy trials for sickle cell disease halted after two patients develop cancer – Science Magazine

Posted: February 17, 2021 at 7:51 am

There are new cancer concerns swirling around a gene therapy approach designed to preventthe sickling of blood cells (above).

By Jocelyn KaiserFeb. 16, 2021 , 6:15 PM

A company has stopped its clinical studies of a promising gene therapy for the blood disorder sickle cell disease after two people who participated developed leukemia-like cancer. Bluebird bio is now investigating whether a virus it uses to deliver a therapeutic gene caused the cancers, reviving old concerns about the risks of this approach.

Its also possible the cancers stemmed from chemotherapy the patients received to prepare their bodies for the genes delivery. This is really a sad development whatever the cause, says Donald Kohn of the University of California, Los Angeles, who has led gene therapy trials for sickle cell and other diseases.

In the bluebird bio trials, scientists remove a patients blood stem cells and treat them in a dish with a modified virus related to HIV. It carries DNA encoding the oxygen-carrying protein hemoglobin and is intended to compensate for the patients defective gene for this molecule. After this step, called ex vivo because a patients cells are treated outside the body, doctors infuse the cells back into the person. Fourteen people who have received the latest version of the bluebird bio therapy are now virtually free of the pain crises their sickled red blood cells once caused.

But today came thenewsthat a patient treated 5 years ago in one of the studies has developed acute myeloid leukemia (AML). Another has myelodysplastic syndrome (MDS), which can develop into AML. A previous patient in the same studydeveloped MDS in 2018, but tests showedit had likely resulted from the DNA-damaging chemotherapy that wipes out a patients blood cells to make room for treated blood cells.

Still, the gene therapy could play a more direct role. In past small clinical trials, several boys with an inherited immune disorder who received similar ex vivo gene therapy developed leukemia. In those cases, a mouse virus ferrying a curative gene into cells landed its genetic cargo in a location that turned on a cancer gene. Researchers then switched to a potentially safer delivery system, a lentivirus that also inserts the genes it carries into the hosts DNA but in sites less likely to trigger a cancer gene. A 2019 report that a monkey treated with a lentiviral gene therapy had developed a leukemia-like condition suggested, however, that thecancer risk had not been eliminated.

Bluebird biotold investors todaythat although its scientists have found the virus inserted DNA into the chromosomes of the leukemia cells of the treated sickle cell patient with AML, they dont yet know its location. Theyll look to see whether the viral DNA landed near a known cancer-promoting gene, perhaps driving its activity. The company says these tests should take a matter of weeks.

Meanwhile, bluebird bio has also halted sales in Europe of an approved treatment that uses the same vector to treat the blood disorder beta-thalassemia. The companys stock price plunged 38% today.

Another sickle cell disease clinical trial that uses the CRISPR gene-editing tool to turn on a fetal form of hemoglobinreported promising results last year. That treatment doesnt rely on a virus to deliver CRISPR; instead, it uses a zap of electricity to get CRISPR editing molecules into cells in a dish. However, CRISPR itself can make off-target effects and rearrange chromosomes, and whether that can trigger cancer may not be known for several years.

The bluebird bio news comes on the heels of a December 2020 report thata patient in a gene therapy trial for hemophilia had developed a liver tumor. The company, uniQure, planned to explore the possible role of its vector, an adeno-associated virus (AAV). Even though AAVs are supposed to be safer than lentiviruses for gene therapy because they are not designed to insert their cargo into a cells genome, animal studies have found they sometimes can.

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Gene therapy trials for sickle cell disease halted after two patients develop cancer - Science Magazine

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