A father’s hug. A mother’s caress. For children with severe combined immunodeficiency, or SCID, the embrace of a family member could be life threatening. Without treatment, most children with this rare immune disease die within the first two years of life.
Children with SCID lack the immune cells necessary to protect them from infection. In the 1980s, the media dubbed SCID as “bubble boy disease,” in reference to a child who spent his brief life inside a sterile chamber to avoid infection. Between 40 and 100 infants in the U.S. are born with the disorder each year.
In 2013, Jose Orellana was one of those children. When a lingering ear infection failed to respond to antibiotics, a blood test revealed SCID. The 9-month-old needed a bone marrow transplant as soon as possible. Upon arrival at St. Jude Children’s Research Hospital, he was rushed to the ICU. Doctors fought to contain his dangerous respiratory infection while seeking a bone marrow donor.
“Jose was put in a plastic chamber completely in isolation,” recalls his mom, Rosalina Orellana. “He received a special breathing treatment designed to kill the bacteria in his body and lungs. It was terrifying. I didn’t know if he was going to survive.”
Thankfully, an anonymous bone marrow donor was the perfect match for Jose, who is one of 13 SCID patients to have received transplants at St. Jude in the past few years. Today, Jose is an active 3-year-old who loves to play outside and interact with other people. When his mom recently learned St. Jude had developed a gene therapy treatment that may be safer and more effective than previous therapies, she was delighted.
“I can’t tell you how elated I am for all the other children who have this disease,” she says. “It’s going to give them so much hope.”
The challenges of transplant
In April 2016, St. Jude scientists and their collaborators unveiled results of a study suggesting that a new kind of gene therapy is safe and effective for children with SCID-X1. Caused by a mutation in the IL2RG gene, SCID-X1 is the most common form of SCID.
In the past, bone marrow transplantation has been the most effective treatment for SCID. Through a transplant, a patient receives healthy blood stem cells from a donor. Once those blood-forming cells enter the bone marrow, they begin to create new, infection-fighting cells.
A transplant has the highest chance of success if the donor and the patient have matching tissue types. Unfortunately, two-thirds of SCID patients lack fully matched donors. Generally, these children do not fare as well, with a third developing immune problems several years after transplant.
Enter gene therapy
To find a safer and more effective process for curing children with SCID, scientists turned to gene therapy. The process provides patients with the normal gene they lack. A carrier molecule known as a vector ferries the normal gene into the patient’s blood-producing stem cells. After infecting the cells, the virus’ work is done, and it dies.
For more than a decade, St. Jude researchers have been toiling to perfect gene therapy. They developed tests to gauge vector safety. They re-engineered a lentivirus to transport the healthy gene into the body. And they created an entirely new process for manufacturing the vector in the Children’s GMP, LLC, an on-site facility that produces biological products and drugs in accordance with federal safety regulations.
“Designing the vector took a couple of years; testing it for safety took two or three more,” reflects Brian Sorrentino, MD, director of St. Jude Experimental Hematology. “And developing the safety data that led to FDA approval took five or six years. As a matter of fact, the Investigational New Drug application we submitted to the FDA was 4,000 pages long.”
Mike Meagher, PhD, president of the GMP facility, reflects on the teamwork necessary to develop and manufacture vector for a project of this magnitude.
“We have 42 full-time staff, and everyone in the building played a role in the development and production of this vector,” he says. “We take a lot of pride in what we do, and it’s pretty cool when we get to see our products make a difference in the life of a child.”
The goal of all that work was to create a gene therapy process that would save young lives. A recent clinical trial offered this option to a group of patients between 7 and 23 years of age for whom standard bone marrow transplant had failed. The results were astounding.
Previous gene therapy trials corrected only white blood cells called T cells. But the new treatment also corrected B cells and natural killer cells, which are crucial parts of the immune system.
“We saw very high levels of correction—unprecedented levels for gene therapy,” Sorrentino says.
The adolescents and young adults in the study were treated at the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health (NIH). All of the patients had undergone bone marrow transplants that had failed to correct their immune function. In addition to using the lentiviral vector developed at St. Jude, the therapy included the first use in SCID of a chemotherapy drug called busulfan. This drug helps make room for the gene-corrected stem cells in the bone marrow.
Patients in the study experienced dramatic improvements as a result of the gene therapy. Although additional follow-up is necessary to confirm long-term effects, Sorrentino is optimistic.
“This rescue of the older children really had phenomenal results,” he says. “All of the patients in the NIH study had transplants that failed, and we salvaged those transplant failures with gene therapy.
“It kind of turns things on their head.”
We saw very high levels of correction—unprecedented levels for gene therapy.
Heading off immune problems
The next step is to offer this therapy to infants with SCID, before chronic infections have a chance to take a toll. A clinical trial using the new gene therapy process is now open at St. Jude for infants with SCID-X1 who lack matched sibling donors. Sorrentino is leading the project with Ewelina Mamcarz, MD, of St. Jude Bone Marrow Transplantation and Cellular Therapy, in conjunction with pediatric immunologist Jay Lieberman, MD, of Le Bonheur Children’s Hospital.
As part of the study, doctors will first extract bone marrow cells from each participant. The infant will receive busulfan chemotherapy while scientists in the GMP treat the donated bone marrow cells with the lentiviral vector. Cells containing the corrected gene will then be infused back into the child’s body. As the cells move into the bone marrow, they will create a new, healthy immune system. Children in the study will remain in the St. Jude Transplant Unit until their immune systems recover.
The hospital recently garnered national attention for its work with SCID. Earlier this year, St. Jude was designated a clinical center in the federally funded Primary Immune Deficiency Treatment Consortium, whose goal is to improve the outcome of patients with inherited immune disorders. And a conference in June of 2016 brought the world’s top SCID researchers to campus to share the latest findings about newborn screening and treatment options.
After more than two decades of work on gene therapy, Sorrentino is enthusiastic about the future of children born with SCID.
“We believe it’s possible that this new form of gene therapy will offer them the best available treatment for their disorder,” he says. “And that’s really exciting.”