Second-generation gene therapy works in bubble boy (SCID) without risk of leukemia

X-linked severe combined immunodeficiency (X-连锁严重联合免疫缺陷病, SCID-X1) is a genetic disorder caused by mutations in the gene encoding the interleukin-2 receptor γ chain (IL2RG). Deficiency in interleukin signaling results in a near complete failure of the immune system. The prevalence of SCID is around 1 in 100,000 births.

Children with SCID are born without an effective immune system, thereby living at high risk of fatal infections. The disease is also known as bubble boy disease (气泡男孩症) because patients should be isolated in the sterile bubbles to prevent infections. The “bubble boy” became widely known because of The Boy in the Plastic Bubble, a movie first aired in 1976.

The most common treatment for SCID is bone marrow transplantation. At the beginning of this century, gene therapy has been attempted in patients who do not have matched donors. It was the first condition to be treated with gene therapy.

In previous trials, infants with were treated with autologous bone marrow cells transduced with a first-generation retrovirus vector carrying healthy IL2RG gene and viral enhancer sequences[1]. Gene therapy successfully restored immunity.

Unfortunately, 25% of gene therapy treated patients developed acute lymphoblastic leukemia. Insertion of the vector increased oncogene (e.g., LMO2, CCND2 and BMI1) expression[2,3], as a result of retrovirus enhancer activating neighboring promoters.

In the second-generation retrovirus vector (self-inactivating retrovirus vector, SIN vector), the viral enhancer was deleted and IL2RG transcription was driven by human elongation factor-1α (EF1α) promoter, greatly decreasing the genotoxic risk[4].

In the ongoing phase I/II trial[5], eight of the nine children have survived, and seven have restored immunity, with a median follow-up of 29.1 months. There was no evidence of leukemia in patients treated with the SIN vector.

Because leukemia was seen at a median of 33 months after gene therapy in the initial trial, long-term follow-up will be warranted to clarify the safety concerns. We need more patients and more time. Other second-generation vectors, particularly SIN lentiviral vectors used for gene therapy are also worth expecting.

[1] Science. 2000, 288(5466), 669-672.

[2] Science. 2003, 302(5644), 415-419.

[3] J Clin Invest. 2008, 118(9), 3132-3142.

[4] Mol Ther. 2008, 16(4), 718-725.

[5] N Engl J Med. 2014, 371(15), 1407-1417.

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