Successful Gene Therapy for Sickle Cell Disease / by F. Perry Wilson

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In what can only be described as a breakthrough in the treatment of sickle cell disease, French researchers are reporting the successful use of gene therapy to cure an afflicted child.

Appearing in the New England Journal of Medicine, the case report documents a 13-year old boy, with severe sickle-cell disease. His first sickle-cell crisis was at age 2, and he’d been receiving exchange transfusions since age 10. Due to his disease, he had bilateral hip osteonecrosis, splenectomy and cholecystectomy.

Prior to this report, the only curative therapy for sickle-cell disease was allogeneic bone marrow transplant. But few patients have matching donors, and even if a match is found, lifelong immunosuppression is necessary to prevent rejection. Gene therapy is the future. Here’s how it was done.

First, the researchers harvested stem cells from the child’s bone marrow.  These stem cells were exposed to a lentivirus vector containing an alternate hemoglobin gene.  Now, here is where it gets really clever. You’d expect that they just put the normal hemoglobin A gene in there, but they didn’t. Instead, they inserted a variant of hemoglobin A with a glutamine-threonine amino acid substitution. This variant has anti-sickling properties. In fact, the variant was discovered in some kids who were expected to have sickle-cell disease but never manifested symptoms.

This is fighting fire with fire. Use a mutated hemoglobin A gene to combat a mutated hemoglobin A gene.

Now, once the gene is transfected, the child still needed to undergo myeloablative therapy, in this case with busulfan. Then his own, now modified, stem cells were given back to him. This is all easier said than done. It was a 50 day hospitalization, 38 days of which were spent without any neutrophil engraftment.

That said, take a look at these results:

What you’re looking at here are the levels of various types of hemoglobin after the therapy. The blue line is normal hemoglobin A, that’s all from transfusions he had received – it disappears once he stops getting transfusions.  In black and green are the percentages of sickle hemoglobin and modified hemoglobin A, about 50:50 each, even 15 months out.

More important than that, he required no further transfusions, had no sickle-cell crises, and had normalization of a host of other biologic parameters. The researchers are too cautious to say this, but he was essentially cured.

Of course, there are still questions for the future.  Will the hemoglobin variant persist years from now? Will the gene insertion increase his chance of blood-borne cancers?  But let’s not lose sight of what has been achieved. A 13-year old boy, who has spent his entire life dealing with the complications of a terrible disease, just got his life back.