Gene therapy restores immunity in infants with rare genetic disease

Gene therapy restores immunity in infants with rare genetic disease

Gene therapy could safely correct the immune systems of infants born with a life-threatening inherited disorder called X-linked severe combined immunodeficiency (X-SCID), reported a new study published in The New England Journal of Medicine.

X-SCID often called “bubble boy disease” is an immunodeficiency disorder caused by a mutation in IL2RG gene making the patient highly susceptible to severe infections. If untreated the disease could become fatal usually within the first year or two of life. It is treated using allogeneic hematopoietic stem-cell transplantation. However, failure to obtain a matching sibling donor often makes it difficult to effectively reconstitute immunity in these patients unless high doses of chemotherapy is given.

To restore immune function in the infants, researchers at National Institute of Allergy and Infectious Diseases (NIAID) and St. Jude Children’s Research Hospital in Memphis, Tennessee, developed an experimental gene therapy that used a modified lentivirus as a vector to deliver normal IL2RG gene into the patient’s own blood-forming stem cells.The trial enrolled eight infants aged 2 to 14 months who were newly diagnosed with X-SCID and lacked a genetically matched sibling donor.

The gene therapy approach utilized blood-forming stem cells from a patient’s bone marrow. An engineered lentivirus was used as a carrier to deliver the normal IL2RG gene to the cells. The stem cells were then infused back into the patient. The patient received a low dose of chemotherapy medication busulfan to help the genetically corrected stem cells establish themselves in the bone marrow and begin producing new blood cells.

The study showed the development of normal numbers of immune cells including T cells, B cells and natural killer (NK) cells within three to four months after gene therapy in seven of the eight infants. While the eighth participant initially had low numbers of T cells, the numbers enhanced following a second infusion of the genetically modified stem cells. Viral and bacterial infections that participants had prior to treatment resolved afterwards. The experimental gene therapy was safe overall, according to the researchers, although some participants experienced expected side effects such as a low platelet count following chemotherapy.

However, previously tested gene-therapy strategies for X-SCID, using γ-retroviral vectors and chemotherapy regimens have appeared less effective compared to the current approach which appears safer and more effective. In these earlier studies, gene therapy restored T cell function but did not fully restore the function of other key immune cells, including B cells and NK cells. Moreover, some participants in certain early gene therapy studies were reported to be complicated by developing vector-related leukaemia. The lentiviral vector used in the study, however, was designed to avoid this problem.

In the current study, participants showed to develop NK cells and B cells. Four infants were also able to discontinue treatment with intravenous immunoglobulin infusions of antibodies which is used to boost immunity. Three of the four developed antibody responses to childhood vaccinations — an indication of robust B-cell function.

Researchers are continuing to monitor the infants who received the lentiviral gene therapy to evaluate the durability of immune reconstitution and assess potential long-term side effects of the treatment.

“These exciting new results suggest that gene therapy may be an effective treatment option for infants with this extremely serious condition, particularly those who lack an optimal donor for stem cell transplant.” said Anthony S Fauci, M.D., director of NIH’s National Institute of Allergy and Infectious Diseases (NIAID) in a press release.

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