Gene therapy uses HIV virus to cure ‘bubble boy’ disease

Therapy has cured 10 infants with no side effects and experts hope this development template will be used for other blood disorders

Gene therapy developed at St Jude Children’s Research Hospital that used HIV as a vector has cured ten infants born with X-linked severe combined immunodeficiency (SCID-X1), or ‘bubble boy’ disease.

The children are producing functional immune cells, including T cells, B cells and natural killer (NK) cells, for the first time. The results were published in 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, of the St. Jude Department of Bone Marrow Transplantation and Cellular Therapy.


The experimental gene therapy was produced in the Children’s GMP a facility located on the St Jude campus operating GMP and was developed by Brian Sorrentino, of the St. Jude Department of Hematology, who was the senior author who 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, a UCSF professor of pediatrics and principal investigator of the trial at UCSF, where four of the infants were treated.

Treatment delivery

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.

Patients with infections prior to gene therapy have recovered. All are developing and growing normally and most patients were discharged from the hospital within one month.

The road to success

Currently, the best treatment for SCID-X1 is bone marrow transplantation with a tissue-matched sibling donor. But more than 80%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 previous attempt at gene therapy to treat this disease was linked with the development of leukaemia. This side-effect has been avoided in its latest incarnation, with no patients developing the blood and bone marrow cancer.

“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 modelled 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 some 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 leukaemia 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, chair of the St Jude Department of Bone Marrow Transplantation and Cellular Therapy. He and Mamcarz are principal investigators of the trial.