X-linked severe combined immunodeficiency disease(X-SCID)is a rare inheriteddisease caused by mutations in the interleukin 2 receptor subunit gamma gene(IL2RG),whichencodes the common g chain protein,a subunit of the ...X-linked severe combined immunodeficiency disease(X-SCID)is a rare inheriteddisease caused by mutations in the interleukin 2 receptor subunit gamma gene(IL2RG),whichencodes the common g chain protein,a subunit of the receptor for lymphocytes.X-SCID ischaracterized by profound defects in T-cell,B-cell,and natural killer cell function.Here,we report a Chinese cohort of nine X-SCID patients with six novel IL2RG mutations.Amongthose,the two adolescent patients with an atypical immunotype were confirmed by furtheranalyzing IL-2-JAK-STAT5 signaling,T cell proliferation,and T cell receptor excision circles(Trecs).Interestingly,Bacillus Calmette-Guerin(BCG)disease occurred commonly in thiscohort.Although allogeneic hematopoietic stem-cell transplantation is curative for the disease,it is not available to all patients due to the lack of suitable matched donors.Autologousgene therapy using a self-inactivating lentiviral vector(SIN-LV)technology has provided analternative therapy for such mono-genetic diseases.Here,we performed the pre-clinicalstudies to assess our SIN-LV carrying IL2RG on human ED7R cells deficient in IL2RG andCD34^(+)stem cells derived from the bone marrow of a healthy donor and a patient with X-SCID.This work is done complied with the established“Good Manufacturing Practice”(GMP)used inthe clinical trials.In addition,a safety study is performed using the transduced CD34^(+)cells implanted into the axilla of nude mice in vivo.Overall,our studies have demonstrated the efficiency and safety of SIN-IL2RG-LV,which paves the way for conducting X-SCID gene therapyclinical trials in China in the near future.展开更多
基金supported by the National Natural Science Foundation of China(No.82070135)the National Key R&D Program of China(No.2021YFC2700804)the CQMU Program for Youth Innovation in Future Medicine(China)(No.W0100).
文摘X-linked severe combined immunodeficiency disease(X-SCID)is a rare inheriteddisease caused by mutations in the interleukin 2 receptor subunit gamma gene(IL2RG),whichencodes the common g chain protein,a subunit of the receptor for lymphocytes.X-SCID ischaracterized by profound defects in T-cell,B-cell,and natural killer cell function.Here,we report a Chinese cohort of nine X-SCID patients with six novel IL2RG mutations.Amongthose,the two adolescent patients with an atypical immunotype were confirmed by furtheranalyzing IL-2-JAK-STAT5 signaling,T cell proliferation,and T cell receptor excision circles(Trecs).Interestingly,Bacillus Calmette-Guerin(BCG)disease occurred commonly in thiscohort.Although allogeneic hematopoietic stem-cell transplantation is curative for the disease,it is not available to all patients due to the lack of suitable matched donors.Autologousgene therapy using a self-inactivating lentiviral vector(SIN-LV)technology has provided analternative therapy for such mono-genetic diseases.Here,we performed the pre-clinicalstudies to assess our SIN-LV carrying IL2RG on human ED7R cells deficient in IL2RG andCD34^(+)stem cells derived from the bone marrow of a healthy donor and a patient with X-SCID.This work is done complied with the established“Good Manufacturing Practice”(GMP)used inthe clinical trials.In addition,a safety study is performed using the transduced CD34^(+)cells implanted into the axilla of nude mice in vivo.Overall,our studies have demonstrated the efficiency and safety of SIN-IL2RG-LV,which paves the way for conducting X-SCID gene therapyclinical trials in China in the near future.
