FDA Places Clinical Hold On Sickle Cell Gene Therapy
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The FDA placed a clinical hold on two gene therapy trials for sickle cell disease (SCD) after two recent complications: one participant developed acute myeloid leukemia (AML) and another developed myelodysplastic syndrome (MDS). The sponsoring company, bluebird bio, suspended the trials last week upon learning of the cases.

The gene therapy "space" is one with spectacular successes — for a form of retinal blindness and spinal muscular atrophy — rising against a backdrop of recent setbacks and failures — for Duchenne muscular dystrophy, lipoprotein lipase deficiency, and myotubular myopathy.

- A Lentiviral Vector
The retooled lentivirus used in the SCD trials, LentiGlobin delivers a beta globin gene with one amino acid replacement to hematopoietic stem cells outside the patient's body. The modified cells are then infused back into the patient.

In 2001, five boys being treated for an inherited immunodeficiency with a gamma retroviral vector developed leukemia and one died. Happening 2 years after the death of 18-year-old in another gene therapy trial, the trial had a chilling effect on the field. Lentiviral vectors have been successful as the backbone of CAR-T therapy, which directs modified T cells to certain blood cancers.

- Pinpointing Causality

At bluebird bio, investigation into the possible "genetic gymnastics" of the lentivirus vector is focusing on where it integrates into the genome — whether it harpoons an oncogene like the gamma retroviral vectors, or affects genome stability. To be causative, the affected gene must be a "driver" of the cancer, and not just a passenger.

Another suspect is busulfan, a drug used to condition the recipient's bone marrow, making room for modified stem cells. "It's possible that busulfan is the main problem, as it is a carcinogen unto itself.

In addition to the two more recent reports of complications, a third trial participant, who had participated in a phase 1/2 trial, developed MDS in 2018 and died of AML last July. The cancer cells from that patient did not contain viral vectors and the MDS was attributed to busulfan conditioning.

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