Rare Daily Staff

St. Jude Children’s Research Hospital said a gene therapy developed there has “cured” infants born with X-linked severe combined immunodeficiency, a rare, life-threatening genetic disorder that is sometimes called “bubble boy” disease.

Severe combined immunodeficiency (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. However, 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 SCID-X1 and more likely to lead to serious treatment-related side effects.

A study of ten infants who received the experimental gene therapy shows that they are producing functional immune cells, including T cells, B cells and natural killer cells, for the first time. The patients were treated at St. Jude and UCSF Benioff Children’s Hospital San Francisco as part of an ongoing clinical trial of infants newly diagnosed with SCID-X1, the most common type of SCID. The results of a study 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,” said first and corresponding author Ewelina Mamcarz of the St. Jude Department of Bone Marrow Transplantation and Cellular Therapy. “This is a first for patients with SCID-X1.”

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 protocol for treating the patients included 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. 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.

“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 Mort Cowan, co-author and a UCSF professor of pediatrics and principal investigator of the trial at UCSF, where four of the infants were treated.

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.

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 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.

The research was funded in part by the California Institute of Regenerative Medicine; the National Institutes of Health; the Assisi Foundation of Memphis; and ALSAC, the fundraising and awareness organization of St. Jude.

The therapy was developed in research led by the late Brian Sorrentino, of the St. Jude Department of Hematology. He is the senior author and died after the manuscript was submitted for publication.

Photo: Gael, a boy who participated in the St. Judge gene therapy trial, with his mother

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