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St. Jude gene therapy cures babies with 'bubble boy' disease

Infants with X-linked severe combined immunodeficiency have fully functioning immune systems following treatment with gene therapy developed and produced at St. Jude Children’s Research Hospital

Memphis, Tennessee, April 17, 2019

Patient Gael with his mother

For patients like Gael, the gene therapy makes moments like this with his mother possible. He and others treated on the St. Jude trial have developed fully functioning immune systems.

Gene therapy developed at St. Jude Children’s Research Hospital has cured infants born with X-linked severe combined immunodeficiency (SCID-X1). The children are producing functional immune cells, including T cells, B cells and natural killer (NK) cells, for the first time. The results appear in the April 18 issue of the New England Journal of Medicine.

“These patients are toddlers now, who are responding to vaccinations and have immune systems to make all immune cells they need for protection from infections as they explore the world and live normal lives. This is a first for patients with SCID-X1,” said first and corresponding author Ewelina Mamcarz, M.D., of the St. Jude Department of Bone Marrow Transplantation and Cellular Therapy.

The patients were treated at St. Jude and UCSF Benioff Children’s Hospital San Francisco with gene therapy produced in the Children’s GMP, LLC, a Good Manufacturing Practice facility located on the St. Jude campus. The children were enrolled in an ongoing clinical trial of infants newly diagnosed with SCID-X1, the most common type of SCID, a rare, life-threatening genetic disorder that is sometimes called “bubble boy” disease. The name is a reference to measures taken to protect patients, who are born with little or no immune protection. Untreated, patients usually die early in life.

Ten infants have received the experimental therapy. It was developed in research led by the late Brian Sorrentino, M.D., of the St. Jude Department of Hematology. He is the senior author and died after the manuscript was submitted for publication.

UCSF played an instrumental role in the St. Jude protocol by including targeted dosing of busulfan, a chemotherapy agent commonly used in bone marrow transplantation to make space in the marrow for donor stem cells to grow. “We found that the addition of very low doses of busulfan based on a model developed at UCSF increased engraftment of gene-corrected stem cells in the bone marrow without causing the side effects associated with standard doses,” said co-author Mort Cowan, M.D., a UCSF professor of pediatrics and principal investigator of the trial at UCSF, where four of the infants were treated.

Bubble boy disease

SCID is caused by a mutation in the interleukin-2 receptor subunit gamma (IL2RG) gene that produces a protein essential for normal immune function.

Currently, the best treatment for SCID-X1 is bone marrow transplantation with a tissue-matched sibling donor. But more than 80 percent of SCID-X1 patients lack such donors. They must rely on blood stem cells from other donors. This process is less likely to cure the SCID-X1 and more likely to lead to serious treatment-related side effects.

The gene therapy involved collecting patients’ bone marrow, then using a virus as a vector to insert a correct copy of the IL2RG gene into the genome (DNA) of patients’ blood stem cells. The cells were then frozen and underwent quality testing. Prior to the gene-corrected blood stem cells being infused back into patients, the infants received two days of low-dose busulfan with the doses individually determined based on each patient’s specific ability to process the drug.

Gene therapy results

Most patients were discharged from the hospital within one month.

Within three months of treatment, gene-corrected immune cells were present in the blood of all but one patient, who required a second dose of gene therapy. The immune cells included T cells and NK cells, which help to fight infections. Antibody-producing B cells were also present, a first for SCID-X1 infants treated with gene therapy.

Patients with infections prior to gene therapy have recovered. All are developing and growing normally. None has developed a life-threatening infection since receiving gene therapy, an indication of treatment effectiveness. No patients have developed leukemia, a side effect of previous gene therapy for SCID-X1.

“While longer follow-up is needed to assess any late effects of treatment, these results suggest most patients treated with this gene therapy will develop a complete durable immune response without side effects,” Cowan said.

Re-imagining gene therapy

St. Jude gene therapy is modeled on the human immunodeficiency virus, a lentivirus that can infect cells that are not dividing. Researchers have re-engineered the lentivirus to ferry a normal copy of IL2RG into patients’ blood stem cells and to be self-inactivating.

In addition to targeted dosing of busulfan, St. Jude gene therapy differs from those earlier gene replacement efforts in several key ways:

  • The vector includes insulators to block activation of genes adjacent to where IL2RG is inserted into patients’ DNA. The goal is to prevent gene therapy from inadvertently causing leukemia by switching on an oncogene in the patient’s blood stem cells.
  • Vector production and gene therapy treatment were streamlined using a stable producer cell line and cryopreservation. Both are important steps for expanding access to treatment and commercializing production.

“This study marks the first time a lentivirus vector and targeted low-dose busulfan have been used as a primary treatment for newly diagnosed infants with SCID-X1,” Mamcarz said.

“We hope this therapy, which includes several novel features, will serve as a template for developing gene therapy to treat other devastating blood disorders,” said co-author Stephen Gottschalk, M.D., chair of the St. Jude Department of Bone Marrow Transplantation and Cellular Therapy. He and Mamcarz are principal investigators of the trial.

The other authors are Sheng Zhou, Timothy Lockey, Hossam Abdelsamed, Shane Cross, Guolian Kang, Zhijun Ma, Jose Condori, Jola Dowdy, Brandon Triplett, Chen Li, Gabriela Maron, Xing Tang, William Janssen, Byoung Ryu, Mitchell Weiss, Benjamin Youngblood and Michael Meagher, all of St. Jude; Juan Carlos Aldave Becerra of Hospital Nacional Edgardo Rebagliati Martins, Peru; Joseph Church, Children’s Hospital Los Angeles; Elif Dokmeci, University of New Mexico; James Love, University of Oklahoma Health Sciences Center, Tulsa; Ana Carolina da Matta Ain, University of Taubaté, Brazil; Hedi van der Watt, Copperfield Childcare, Claremont, South Africa; Suk See De Ravin and Harry Malech, both of the National Institute of Allergy and Infectious Diseases; and Janel Long-Boyle and Jennifer Puck of UCSF.

The research was funded in part by the California Institute of Regenerative Medicine (CLIN2-09504); grants (HL053749, AI00988, AI082973, CA21765) from the National Institutes of Health; the Assisi Foundation of Memphis; and ALSAC, the fundraising and awareness organization of St. Jude.

St. Jude Children's Research Hospital

St. Jude Children's Research Hospital is leading the way the world understands, treats and cures childhood cancer and other life-threatening diseases. It is the only National Cancer Institute-designated Comprehensive Cancer Center devoted solely to children. Treatments developed at St. Jude have helped push the overall childhood cancer survival rate from 20% to 80% since the hospital opened more than 50 years ago. St. Jude shares the discoveries it makes, and every child saved at St. Jude means doctors and scientists worldwide can use that knowledge to save thousands more children. To learn more, visit or follow St. Jude on social media at @stjuderesearch.