A Gene Therapy Triumph for "Bubble Boy" Children
Regina Kelder

A Gene Therapy Triumph for "Bubble Boy" Children

Using a disabled HIV virus, doctors corrected a rare inherited disorder in infants without a functional immune system

Two years ago, the US Food and Drug Administration approved a gene therapy drug for a rare form of leukemia. The cancer immunotherapy drug, developed by scientists from University of Pennsylvania in partnership with Novartis, was the first gene therapy to be approved in the US.

But it’s in the realm of inherited disorders where much of the action has been occurring. The FDA recently approved a drug that can reverse a rare form of inherited vision loss. And gene therapy is showing promise for ending one form of hemophilia.

Now researchers from St Jude’s Children’s Research Hospital have cured 10 infants with a rare disorder called X-linked severe combined immunodeficiency disorder (SCID-XI), otherwise known as the Bubble Boy disease. The condition is caused by a single mutation that leaves them without any immunological armor to fend off foreign pathogens. They are a target the day they are born.

St. Jude’s said that their team used a disabled HIV virus to shuttle in a correct copy of the gene into blood-producing cells. The vector included safety features that prevented the off-target effect. The findings, reported this week in the New England Journal of Medicine showed that 16 months after the gene therapies were performed, functional T cells and B cells were reconstituted along with normalization of natural killer cell counts. The children who received the gene therapy also received low-dose chemotherapy to make room in their bone marrow for the gene-corrected cells.

The first eight SCID-X1 babies treated with the St. Jude gene therapy are all growing normally and making complete sets of immune cells for the first time. None have developed serious infections.

“This treatment offers the first complete cure of babies with SCID-X1,” said Ewelina Mamcarz, MD, of St. Jude Bone Marrow Transplantation and Cellular Therapy in a hospital release. “We hope this combination therapy will be the template for curing other blood disorders.”

Indeed, the breakthrough represents a major step forward for a field that not too long ago suffered enormous losses. When researchers first began attempting gene therapy in the 1980s and 1990s, it was often hyped by media as the Next Big Thing in medicine. But it became highly controversial after an 18-year-old named Jesse Gelsinger, who suffered from a genetic liver disease, died in 1999 during a gene therapy trial at UPENN. The cause of death was attributed to the viral vector—a modified adenovirus-derived vector—that was used to deliver the gene he lacked.

Technologies have since evolved sufficiently to make the strategy a viable alternative for treating a growing number of diseases, but the push forward has still had its setbacks. Fifteen years ago, a gene therapy for SCID-XI was shelved after two children enrolled in a French trial, developed leukemia, prompting US regulators to halt a similar trial in the US.

The fact that scientists now know how to cure children with this immunodeficiency shows how far the field has come in a relatively short period of time. A series of successful clinical trials, such as the one at St. Jude’s, is propelling the field forward. Less problematic vectors are being used to shuttle in DNA to repair gene mutations. And last summer the US National Institutes of Health and the FDA also removed a requirement that gene therapies needed to be reviewed first by the Recombinant DNA Advisory Committee, which had advised the NIH for decades on protocols involving gene therapies in humans.

Still, there are only a handful of gene therapies available on the market despite the thousands of gene therapy trials, indicated just how high the bar is for success. Studies like St. Jude’s shows it can be met.