2017 Innovation Awards Winner – St. Jude Children’s Research Hospital

Innovation: Pioneering gene therapy treatment has succeeded where bone marrow transplants have failed to correct immune function of young cancer patients. The upshot is that now hope exists for patients with “bubble boy disease.”

For children afflicted by severe combined immunodeficiency (SCID), there is no margin for error. A lack of immune cells means that the children are unable to protect themselves from infection. Even minimal contact with another human being can be fatal. Most untreated children with SCID die within the first two years of their lives. Until recently, a matching bone marrow transplant from a sibling was the most effective treatment. The problem, however, is that many children do not have a matching donor. With a mismatched transplant, about 30 percent will die before they reach age 10. Past that, teenagers and young adults continue to experience fatal cases of immunodeficiency.

In the 1980’s, SCID was labeled as “bubble boy” disease, a reference to children who were forced to live in a sterile chamber to avoid infection. Between 40 and 100 infants are born with the disease each year. Fast forward to April 2016, and Dr. Brian Sorrentino, along with several colleagues from St. Jude Children’s Research Hospital, revealed study results that suggested a new safe and effective form of gene therapy treatment for patients with SCID-X1, the most common strain of SCID.

Gene therapy hadn’t been truly effective until then. Sometimes it would lead to a patient contracting leukemia. But St. Jude’s process, perfected over a 10 year period, has seen remarkable results. By combining lentivirus gene therapy, which uses a lentiviral vector to deliver a healthy gene into a host, with busulfan, a chemotherapy drug, doctors were able to rebuild the immune system and develop broader immunity in five young adults with the disorder.

The entire process included managing tests for vector safety, re-engineering a lentivirus to safely transport a healthy gene into a new host, and creating an entirely new way of manufacturing vectors. That last element is key for the treatment, and the solution was very surprising. “What we shifted to is using the AIDS virus,” Sorrentino says. “We take all of the AIDS genes out of the virus and just use the shell as a trojan horse for delivering the gene that’s broken and causes the SCID.”

The AIDS-derived virus was crafted into St. Jude’s lentivirus, which, after copious testing and studies, proved to a be a safer way to to conduct the therapy. “It turns out that these AIDS-derived viruses, which we call lentiviral vectors, are much safer and much more effective for gene therapy,” he says. “Think about it for a second: what is the AIDS virus good at? It’s good at infecting humans. We exploit that property, because getting genes and bone marrow stem cells is not easy.”

The next challenge was tailoring busulfan to young children. After the first positive trials, St. Jude researchers moved on to infants. It was imperative to make sure that the drug was dosed precisely based on a patient’s age and weight. Working with another team at the University of San Francisco, a computer algorithm takes the blood levels and then decides what the second dose should be. “All of the kids have exactly the blood level we want to achieve, and that’s never been done with SCID before.”

With precise busulfan dosage and vectors produced in-house, the research can be conducted at any time. The new process, which has so far been used to treat SCID, has the potential to be used for other diseases as well. “No one has ever used this technology to produce vectors before. We think this is going to be something that’s the wave of the future.”

There is a wide variety of possible options, but St. Jude is looking at the possibility of using it to treat Sickle-Cell Disease, a prominent issue in Memphis. Other types of immunodeficient diseases can be treated as well, and Sorrentino says that any disease of the blood system caused by known genetic defects is amenable to this approach.

St. Jude has now treated six infants with the immunodeficiency gene therapy program. The two youngest began treatment at two-months, while the oldest was less than a year old. Most of the patients have displayed signs of a full recovery, with immune signs coming back and doctors getting great immune signs from them.

“This protocol allows us to treat up to 28 cases. If we continue to do these cases and learn, eventually this is a treatment we would like to see commercialized. We’ve been talking to a number of biopharmaceutical companies that are interested in licensing this from us, and they would eventually conduct a phase 3 trial, making this FDA approved.”

With gene therapy exploding and continued help from sponsors, donors, and big supporters like the Assisi Foundation, that day might not be too far off. For now, though, Sorrentino is focused on his patients. The second of Sorrentino’s trial patients, from Peru, returned home after six months and was immunologically normal. Thanks to the new gene therapy and vectors manufactured by St. Jude, a once-fatal case of SCID is now a healthy, growing child.