Status of, and challenges in, gene therapy for immunodeficiencies

Sung-Yun Pai, MD

Sung-Yun Pai, MD

Gene therapy has promise as a treatment for children with genetic immunodeficiencies such as X-linked SCID (SCID-X1, so-called "bubble boy syndrome"), and for ADA-SCID is well on the way to becoming the therapy of choice. Children with X-linked SCID and ADA-SCID lack functional T cells, as well as variable defects in other immune system components (e.g., B cells, NK cells).

Sung-Yun Pai, MD, a pediatric hematologist/oncologist at Dana-Farber/Children's Hospital Cancer Center (DF/CHCC), notes that there is a strong rationale for turning to gene therapy for these conditions.

"Gene therapy works best if we can improve symptoms with just a small number of gene corrected cells," she says. "It takes relatively few gene corrected blood stem cells to develop enough normal T cells to cure SCID."

While gene therapy for immunodeficiencies employs the same basic hematopoietic stem cell or bone marrow transplantation techniques used for leukemias and non-malignant blood disorders, Pai explains a couple of significant differences.

"With standard allogeneic hematopoietic stem cell transplants—those where the cells are supplied by a related or unrelated healthy donor—there is always the risk that the patient will reject the transplanted cells or develop graft versus host disease," she says. "With gene therapy transplants, the patient acts as his or her own donor, eliminating those risks. We collect the hematopoietic cells, insert the corrective gene into the cells in the laboratory and infuse the corrected cells back into the patient."

The success stories coming out of recent gene therapy trials in SCID-X1, ADA-SCID and another immunodeficiency disease, Wiskott-Aldrich syndrome (WAS), have been tempered by a severe complication. "Five of the 20 SCID-X1 patients treated with gene therapy thus far have developed T cell acute leukemia because of insertional oncogenesis," Pai says. "The retrovirus used to transfer the corrective gene inserted itself into the patients' DNA in such a way as to activate and overexpress certain oncogenes."

Retroviruses have been the vectors of choice for immunodeficiency gene therapy. They integrate themselves securely into the DNA of patients' hematopoietic stem cells and are passed on to those cells' progeny, ensuring that any new immune cells arising from these progenitors will carry the corrective gene.

Pai notes that there are several strategies that doctors and researchers might use to avoid insertional oncogenesis. "One could use a so-called self-inactivating vector, as we are using in our current study of gene transfer for the treatment of SCID-X1, or use a different type of virus, such as a lentivirus, a strategy we are employing in a new gene transfer trial for children with WAS," she says. "Other options would be to target the vector to known 'safe harbor' sites in the genome, or use in situ techniques to correct the defective gene itself."

For more information about the gene therapy trials noted above please email