FDA places clinical hold on sickle cell gene therapy


The Food and Drug Administration placed a clinical hold yesterday 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 company has also put the brakes on a treatment for beta thalassemia already approved in the European Union and the United Kingdom, betibeglogene autotemcel (Zynteglo). The treatment hasn’t been associated with problems but uses the same gene delivery vector, a lentivirus, as that used in the SCD trials.

Overall, the company has enrolled 47 SCD patients and 63 with beta thalassemia in trials.

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. The gene therapy reshapes red blood cells, enabling them to circulate through narrow blood vessels without sickling and adhering into painful logjams.

What is worrisome is that in the patient who developed AML, and who received the gene therapy more than 5 years ago, the cancer cells contained the vector. Those test results aren’t yet available for the participant who has MDS.

The finding raises suspicion that the gene therapy had a role in the cancer, but is only correlative.

Lentiviral vectors have a good track record, but the two cases evoke memories of 2 decades ago. In 2001, five children being treated for an inherited immunodeficiency (SCID-X1) with a gamma retroviral vector developed leukemia and one died. Those viruses inserted into an oncogene. Happening 2 years after the death of 18-year-old Jesse Gelsinger in another gene therapy trial, the SCID trial had a chilling effect on the field.

Since then, lentiviral vectors have been reinvented to be “self-inactivating,” minimizing the risk for inserting willy-nilly into a genome. “Lentiviral vectors have been expressly designed to avoid insertional oncogenesis, based on prior experience with the gamma retroviruses. We don’t have evidence that the vector is causative, but our studies will shed some light on whether that’s true in these cases,” said bluebird bio chief scientific officer Philip Gregory, DPhil, on a conference call Feb. 16.

Lentiviral vectors have been successful as the backbone of chimeric antigen receptor T-cell (CAR-T) therapy, which directs modified T cells to certain blood cancers. “Among the hundreds to thousands of patients treated with CAR-T cell therapy, lentivirus vector hasn’t been associated with any malignancies,” said bluebird’s chief medical officer, Dave Davidson, MD.

Jeanne Loring, PhD, director of the Center for Regenerative Medicine at Scripps Research, agreed. “Gene therapy is having some extreme highs and lows these days. Most studies use [adeno-associated viral] vectors, which don’t integrate into the genome. But some people have antibodies to AAV vectors, and AAV is diluted out when cells divide. That’s why lentivirus, which integrates into the genome, is used for blood stem cells and T cells in CAR-T therapy.”


Next Article: