September 26, 2012
2 min read

Novel gene therapy shows promise in children with severe combined immunodeficiency

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The addition of chemotherapy to gene therapy improved outcomes in children with severe combined immunodeficiency, according to study results.

Researchers conducted the trial in 10 patients with adenosine deaminase-deficient severe combined immunodeficiency.

The investigators employed two slightly different retroviral vectors for transduction of bone marrow CD34 cells in the analysis.

Four patients did not receive cytoreductive conditioning before reinfusion of transduced bone marrow CD34 cells and continued to receive enzyme replacement therapy. Six patients received non-myeloablative conditioning with busulfan and had enzyme replacement therapy withdrawn.

Peripheral blood mononuclear cells in two older patients — aged 15 and 20 years — demonstrated transient, low-level (<0.01%) gene marking. However, some gene marking of peripheral blood mononuclear cells persisted for 9 years in two younger patients, one of whom was aged 4 years and the other was aged 6 years.

Six other patients received the same gene transfer protocol but only after withdrawal of enzyme replacement therapy and treatment with low-dose busulfan (65 mg/m2 to 90 mg/m2). Three of those patients are no longer receiving enzyme replacement therapy at 5, 4 and 3 years after the procedure. These three patients have demonstrated gene marking in peripheral blood mononuclear cells of 1% to 10% and adenosine deaminase enzyme expression in peripheral blood mononuclear cells near or within normal range, researchers said.

The investigators re-initiated enzyme replacement therapy in two patients due to poor gene marking and immune recovery. One of those patients subsequently underwent hematopoietic stem cell transplant.

“It is now clear that, in order to obtain positive outcomes, gene therapy approaches for ADA-SCID need to include cytoreductive chemotherapy,” researcher Fabio Candotti, MD, senior investigator in the Genetics and Molecular Biology Branch of the National Human Genome Research Institute at the National Institutes of Health, and chair of the ASH Scientific Committee on Immunology and Host Defense, told HemOnc Today.

“In fact, data from two of our patients who re-started enzyme replacement therapy suggest that the administration of busulfan was more important than the withdrawal of PEG-ADA for the long-term presence of gene-corrected, ADA-expressing lymphocytes after gene therapy” Candotti said. “The design of future clinical trials will benefit from these observations.”

Gene therapy for this disease has been successful in Europe, and the study’s results provide the clinical community in the United States an option for gene therapy in these patients, Candotti said.

Donald B. Kohn, MD, director of the Human Gene Medicine Program and a member of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA, suggested the findings provide clinical therapy that can “restore immunity without the risks of graft rejection or graft-versus-host disease from allogeneic HSCT.”

The study results also lay the groundwork for applications to other blood cells diseases, Kohn said.

Kohn noted that the therapy worked only when patients underwent non-myeloablative marrow conditioning prior to transplant.

“Also, it worked best for patients treated as infants rather than later in childhood,” he said.  

Disclosure: The study was supported by grants from Children’s Hospital Los Angeles, the Doris Duke Charitable Foundation and the NHLBI. Candotti and Kohn report no financial disclosures.