Gene therapy restores immune function to infants with SCID-X1 (X-linked severe combined immunodeficiency)

Image of the IL2RG protein discissed in the text.

IL2RG protein, encoded by tL2RG complementary DNA. (

As reported in the 18 April issue of the New England Journal of Medicine, researchers at the St. Jude Children’s Research Hospital (Memphis, TN) and their colleagues have used gene therapy to restore immune function to eight infants with newly diagnosed X-linked severe combined immunodeficiency (SCID-X1).

SCID-X1 is sometimes called “bubble-boy disease”, because of the case of a boy born in 1971 with SCID-X1, who had to be isolated in a plastic bubble while awaiting a bone-marrow transplant.

SCID-X1 is a rare X-linked genetic disease caused by a mutation in the L2RG gene. This gene encodes the interleukin-2 receptor subunit gamma (IL-2RG), which is common to the receptor complexes for at least six different interleukin receptors, including IL-2 and IL-4. Individuals with SCID-X1 produce very few T and NK (natural killer) cells, and are thus severely immunodeficient. As a result, they are very susceptible to infections, and typically die before age 2 if not isolated or treated.

Although SCID-X1 is a rare disease, it is the most common form of severe combined immunodeficiency. It probably affects at least 1 in 50,000 to 100,000 newborns.

SCID-X1 can sometimes be cured by a bone-marrow transplant from a matched sibling donor. However, fewer than 20% of SCID-X1 patients have such an available donor.

A previous attempt to apply gene therapy to treatment of SCID-X1, in the early 2000s, utilized a Moloney murine leukemia virus (MoMuLV) gammaretrovirus as a vector. This resulted in a high level of leukemia induction, as discussed in a previous article on this blog. So this approach had to be abandoned. Instead, researchers have developed lentiviral vectors, which appear to have a lower risk of leukemogenesis than gammaretroviral vectors. We discussed the development and use of lentiviral vectors in our November 2015 book-length report, Gene Therapy: Moving Toward Commercialization, published by Cambridge Healthtech Institute.

The new experimental gene therapy for SCID-X1 utilized a lentiviral vector carrying IL2RG complementary DNA.  This was used to transfect patient-derived bone-marrow stem cells. The transfected stem cells were infused back into eight infants with newly diagnosed SCID-X1after low-exposure, targeted busulfan conditioning. (“Conditioning”, for example via a myelosuppressive chemotherapy like busulfan given prior to stem-cell transplantation, is designed to make room for transplanted blood stem cells to grow.

The eight infants were studied for a median of 16.4 months, and experienced no unexpected side effects. In seven of the infants, the numbers of T cells and NK cells normalized by 3 to 4 months after infusion. The vector was present in T cells, B cells, NK cells, myeloid cells, and bone marrow progenitors in these seven subjects. The eighth subject initially had an insufficient T-cell count. However, a boost of gene-corrected cells without busulfan conditioning resulted in T-cell normalization. Previous infections were cleared in all infants, and all continued to grow normally. The subjects also showed other signs of immune system normalization, including vaccine response in three of the infants.

The researchers concluded that the IL2RG-lentiviral vector gene therapy combined with low-exposure, targeted busulfan conditioning in infants with newly diagnosed SCID-X1 showed low-grade acute toxic effects, and resulted in engraftment of transduced cells, reconstitution of functional T cells and B cells, and normalization of NK-cell counts during a median follow-up of 16 months. Children treated with this gene therapy should therefore be protected against common ailments by their reconstituted immune systems. However, they will still need to be monitored long-term to determine if the treatment is durable and free of side effects over the long term.


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