RARE DISEASE
T-B+ severe combined immunodeficiency due to gamma chain deficiency
T-B+ severe combined immunodeficiency due to gamma chain deficiency
T-B+ severe combined immunodeficiency due to gamma chain deficiency
Synonyms: SCIDX1, T-B+ SCID due to gamma chain deficiency, T-B+ severe combined immunodeficiency, X-linked
Synonyms: SCIDX1, T-B+ SCID due to gamma chain deficiency, T-B+ severe combined immunodeficiency, X-linked
Synonyms: SCIDX1, T-B+ SCID due to gamma chain deficiency, T-B+ severe combined immunodeficiency, X-linked
Drug discovery
2
drugs
With orphan designations
Overview
T-B+ severe combined immunodeficiency due to gamma chain deficiency (SCID-X1) is an X-linked recessive disorder caused by mutations in the IL2RG gene, which encodes the interleukin-2 receptor gamma chain critical for immune cell signaling [1][17]. This results in absent T and natural killer (NK) cells, with B cells present but dysfunctional [1][13]. Infants typically present within the first months of life with severe bacterial, viral, or fungal infections (e.g., Pneumocystis jiroveci), chronic diarrhea, failure to thrive, and graft-versus-host disease from maternal T cells [1][6]. Diagnosis is confirmed via TREC newborn screening, flow cytometry, and genetic testing [1][17].
Therapies
Early hematopoietic stem cell transplantation (HSCT) from HLA-matched donors achieves >90% survival when performed before 3.5 months [6][14].
Gene therapy (experimental) restores immune function in IL2RG-deficient patients without graft-versus-host disease risk [14][6].
Supportive care includes immunoglobulin replacement, antimicrobial prophylaxis, and isolation protocols [1][13].
Categories: rare genetic diseases, rare immunological diseases, rare transplant-related disorders
Research Papers
189 drug discovery papers about T-B+ severe combined immunodeficiency due to gamma chain deficiency, with 3 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
189 drug discovery papers about T-B+ severe combined immunodeficiency due to gamma chain deficiency, with 3 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-07-28 | Prevention of recurrence of severe combined immunodeficiency through preimplantation genetic testing: a case study of a novel IL2RG variant and confirmed maternal somatic mosaicism in Thailand
RESEARCH QUESTION: Can preimplantation genetic testing for monogenic disorders (PGT-M) be effectively implemented to prevent recurrence of X-linked severe combined immunodeficiency (X-SCID) caused by a novel IL2RG variant when conventional parental carrier testing initially yields a negative result? DESIGN: CASE REPORT: A Thai couple with a prior affected child (deceased; T⁻B⁺NK⁻ immunophenotype; IL2RG c.676C > G, p.(Arg226Gly)) underwent whole exome sequencing (WES), which was initially negative in both parents. Subsequent WES reanalysis identified a low-level heterozygous signal (~ 12% allele frequency) in the mother's blood, below the standard 30% calling threshold, consistent with low-level maternal mosaicism. Direct sequencing and PCR-RFLP from buccal swab tissue showed a concordant low-level signal in a second tissue compartment. Six blastocysts obtained via ICSI underwent trophectoderm biopsy for combined PGT-M (targeted to the proband's confirmed variant) and comprehensive chromosomal screening (PGT-A). RESULTS: Four blastocysts were euploid and two aneuploids. Of the euploid embryos, three were mutation-free (wild-type) and one carried the IL2RG c.676C > G variant. A single frozen-thawed embryo transfer of a mutation-free euploid embryo resulted in a confirmed intrauterine pregnancy. Non-invasive prenatal testing (NIPT) at 12 weeks demonstrated low risk for Trisomy 21, 18, and 13, with fetal sex concordant with PGT-A findings. CONCLUSIONS: The novel IL2RG c.676C > G (p.(Arg226Gly)) variant identified at a known mutational hotspot (codon 226) and absent from global variant databases is classified as Likely Pathogenic per ACMG criteria. Low-level maternal mosaicism was subsequently identified in blood and supported by concordant low-level findings in buccal mucosa, clarifying recurrence-risk counselling for this family. PGT-M anchored to the proband's confirmed IL2RG variant successfully identified three transferable, euploid, mutation-free embryos, and transfer of one embryo resulted in an ongoing pregnancy. This case demonstrates that ICSI with PGT-M can prevent X-SCID recurrence even when standard parental carrier testing is initially non-informative, establishing a reproductive workflow applicable to families in whom the proband's variant is confirmed.
2026-07-14 | Base Editing Hematopoietic Stem/Progenitor Cell Gene Therapy for Treatment of X-Linked Severe Combined Immunodeficiency
X-linked Severe Combined Immunodeficiency (XSCID) due to IL2RG loss-of-function mutations typically cause a severe combined cellular and humoral immunodeficiency that is diagnosed and transplanted in infancy. Hypomorphic IL2RG variants with milder phenotypes are generally diagnosed later in life. Early stem cell transplants (allogeneic or autologous gene therapy) performed without conditioning often results in partial immune reconstitution with limited donor engraftment in T cell lineage alone. Defective host B, natural killer (NK), and other cell lineages remain and can cause progressive multi-organ disease. Ex vivo gene therapy using lentivector-transduced autologous hematopoietic stem/progenitor cells (HSPCs) has provided clinical benefit for many previously transplanted older XSCID patients (NCT01306019) and transplant-naïve infants (NCT01512888, NCT03311503). Lentivector transduction functionally corrects XSCID stem cells by semi-random insertion of IL2RG cDNA under the regulation of an engineered promoter. A conversion to gene-corrected immune cells in their respective compartment can take years, particularly in older adult patients. The exact mechanism for this slow progression, whether this is attributable to a relatively weak promoter in the transgenes, is unclear. CRISPR/Cas9 base editing provides the potential for precise gene mutation correction that is devoid of random virus integrations and, critically, restores physiological gene regulation by endogenous promoter. We developed a highly efficient base editing strategy using adenine base editor and respective guide RNAs to repair respective IL2RG mutations (IL2RG p.289X, IL2RG p.Gln235X, IL2RG p.Q144X, and IL2RG p.R226H). Preclinical efficacy and safety data supported a Phase I/II clinical trial to treat XSCID patients with base-edited HSPCs (IND 31037; NCT 06851767). Three patients have been treated to date with base-edited (BE) HSPCs (25 million to 50 million cells per kg/weight). BE HSPC products were well tolerated, with early myeloid recovery within 3 weeks after cell infusion. Gene correction frequencies in the study cell products averaged >80%. Follow-up data at 6 months in the first patient showed robust levels of gene correction in myeloid (70%), B (94%), NK (100%), and, surprisingly, in his T cell compartment (65%) as well, with a corresponding decline in donor T cell chimerism (99% at baseline, 47% at 6 months). Monitoring of the other treated patients is ongoing. We conclude from our preliminary data that gene therapy using BE HSPCs appear very promising for achieving an earlier and more robust multi-lineage immune reconstitution in adult patients using BE HSPCs.
2026-06-30 | Combined immune deficiency caused by a hypomorphic <i>IL2RG</i> variant and disguised as Burkitt leukemia: a clinical case
X-linked severe combined immunodeficiency (X-SCID) is an inborn error of immunity characterized by almost total absence of T and NK cells with normal counts of functionally impaired B cells (T–B+NK–) that is caused by pathogenic variants in the IL2RG gene resulting in early onset of life-threatening infections. Hypomorphic X-SCIDs present with variable clinical features and are characterized by later onset of infectious complications, a wide range of autoimmune manifestations, and increased risk of malignancies. In this article, we report a rare case of atypical X-SCID presenting with partial red cell aplasia and Burkitt leukemia as the first signs of immune dysregulation. Verification of the diagnosis of X-SCID leads to a different treatment approach, including the use of hematopoetic stem cell transplantation as a curative option. It highlights the importance of awareness of inborn errors of immunity among hematologists and oncologists.
2026-06-01 | Gene Therapy As A Treatment Modality For Severe Combined Immunodeficiency : A Narrative Review
Introduction: Severe combined immunodeficiency (SCID) is a life-threatening genetic disorder marked by severe T-cell defects and often B-cell and NK-cell dysfunction, leading to an increased risk of infections. Treated via gene therapy which is the introduction of modified therapeutic genes either ex vivo or in vivo as a DNA segments. Methods: A Narrative review was conducted followed. Literature was searched on MidLine, pubmed central (PMC), Web of science, Elcevier, Scopus using the following keywords: Severe combined immunodeficiency(SCID), gene therapy and genetic disorders between 2015 and 2024. The included papers were case reports and series, cohort studies, case control and randomized controlled trials. Results: The reviewed literature illustrate that gene therapy has reached significant progress in treating (SCID), particularly X-linked SCID (SCID-X1) and ADA-SCID. Viral vectors especially retroviral, lentiviral, and adeno-associated viral (AAV) vectors have been successfully used to recover T-cell immunity and correct genetic defects, with ADA-SCID patients showing stable immune function and reduced adoption on enzyme replacement therapy. The Protection of lentivirus and foamy virus vectors have been improved, reducing dangers like insertional mutagenesis. Despite their biosafety enhancement, non-viral delivery methods are still limited by their lower transfection efficiency. Conclusion: gene therapy has the ability to treat numerous different primary immunodeficiency (PIDs). There are some limits. Important elements to consider are vector and envelope type, transduction technique, cell dose, delivery modality, conditioning regimen, and illness features. Further research is needed.
2026-05-25 | Modeling and correction of SCID-X1 using CRISPR-Cas9 homology-directed repair in human HSPCs.
X-linked severe combined immunodeficiency (SCID-X1) is a severe primary immunodeficiency caused by mutations in the IL2RG gene, a shared subunit of cytokine receptors critical for the development and function of T and natural killer (NK) cells. The standard treatment, allogeneic hematopoietic stem cell transplantation (HSCT), requires a compatible donor and is often associated with significant transplant-related complications. We aimed to develop a more robust and universal gene therapy by ex vivo modification of patient hematopoietic stem and progenitor cells (HSPCs) using the CRISPR-Cas9/rAAV6 gene-editing platform. To evaluate efficiency, we utilized a feeder-free, in vitro platform enabling T and NK cell differentiation from modified HSPCs. We investigated two approaches: the cut-site method (inserting a corrective cassette downstream of the start codon within the IL2RG locus) and a replacement method (replacing the entire IL2RG gene under endogenous regulation). We demonstrated that the cut-site insertion strategy is preferable for SCID-X1 correction, achieving superior homology-directed repair rates, lower toxicity, and significantly improved T and NK cell differentiation, based on phenotypic marker expression. Importantly, corrected patient-derived HSPCs from two SCID-X1 patients, modified using the cut-site approach, successfully demonstrated phenotypic evidence of T cell differentiation. Therefore, our findings firmly establish the feasibility of the cut-site strategy as a universal, high-efficiency, therapeutic solution for SCID-X1.
2026-07-28 | Prevention of recurrence of severe combined immunodeficiency through preimplantation genetic testing: a case study of a novel IL2RG variant and confirmed maternal somatic mosaicism in Thailand
RESEARCH QUESTION: Can preimplantation genetic testing for monogenic disorders (PGT-M) be effectively implemented to prevent recurrence of X-linked severe combined immunodeficiency (X-SCID) caused by a novel IL2RG variant when conventional parental carrier testing initially yields a negative result? DESIGN: CASE REPORT: A Thai couple with a prior affected child (deceased; T⁻B⁺NK⁻ immunophenotype; IL2RG c.676C > G, p.(Arg226Gly)) underwent whole exome sequencing (WES), which was initially negative in both parents. Subsequent WES reanalysis identified a low-level heterozygous signal (~ 12% allele frequency) in the mother's blood, below the standard 30% calling threshold, consistent with low-level maternal mosaicism. Direct sequencing and PCR-RFLP from buccal swab tissue showed a concordant low-level signal in a second tissue compartment. Six blastocysts obtained via ICSI underwent trophectoderm biopsy for combined PGT-M (targeted to the proband's confirmed variant) and comprehensive chromosomal screening (PGT-A). RESULTS: Four blastocysts were euploid and two aneuploids. Of the euploid embryos, three were mutation-free (wild-type) and one carried the IL2RG c.676C > G variant. A single frozen-thawed embryo transfer of a mutation-free euploid embryo resulted in a confirmed intrauterine pregnancy. Non-invasive prenatal testing (NIPT) at 12 weeks demonstrated low risk for Trisomy 21, 18, and 13, with fetal sex concordant with PGT-A findings. CONCLUSIONS: The novel IL2RG c.676C > G (p.(Arg226Gly)) variant identified at a known mutational hotspot (codon 226) and absent from global variant databases is classified as Likely Pathogenic per ACMG criteria. Low-level maternal mosaicism was subsequently identified in blood and supported by concordant low-level findings in buccal mucosa, clarifying recurrence-risk counselling for this family. PGT-M anchored to the proband's confirmed IL2RG variant successfully identified three transferable, euploid, mutation-free embryos, and transfer of one embryo resulted in an ongoing pregnancy. This case demonstrates that ICSI with PGT-M can prevent X-SCID recurrence even when standard parental carrier testing is initially non-informative, establishing a reproductive workflow applicable to families in whom the proband's variant is confirmed.
2026-07-14 | Base Editing Hematopoietic Stem/Progenitor Cell Gene Therapy for Treatment of X-Linked Severe Combined Immunodeficiency
X-linked Severe Combined Immunodeficiency (XSCID) due to IL2RG loss-of-function mutations typically cause a severe combined cellular and humoral immunodeficiency that is diagnosed and transplanted in infancy. Hypomorphic IL2RG variants with milder phenotypes are generally diagnosed later in life. Early stem cell transplants (allogeneic or autologous gene therapy) performed without conditioning often results in partial immune reconstitution with limited donor engraftment in T cell lineage alone. Defective host B, natural killer (NK), and other cell lineages remain and can cause progressive multi-organ disease. Ex vivo gene therapy using lentivector-transduced autologous hematopoietic stem/progenitor cells (HSPCs) has provided clinical benefit for many previously transplanted older XSCID patients (NCT01306019) and transplant-naïve infants (NCT01512888, NCT03311503). Lentivector transduction functionally corrects XSCID stem cells by semi-random insertion of IL2RG cDNA under the regulation of an engineered promoter. A conversion to gene-corrected immune cells in their respective compartment can take years, particularly in older adult patients. The exact mechanism for this slow progression, whether this is attributable to a relatively weak promoter in the transgenes, is unclear. CRISPR/Cas9 base editing provides the potential for precise gene mutation correction that is devoid of random virus integrations and, critically, restores physiological gene regulation by endogenous promoter. We developed a highly efficient base editing strategy using adenine base editor and respective guide RNAs to repair respective IL2RG mutations (IL2RG p.289X, IL2RG p.Gln235X, IL2RG p.Q144X, and IL2RG p.R226H). Preclinical efficacy and safety data supported a Phase I/II clinical trial to treat XSCID patients with base-edited HSPCs (IND 31037; NCT 06851767). Three patients have been treated to date with base-edited (BE) HSPCs (25 million to 50 million cells per kg/weight). BE HSPC products were well tolerated, with early myeloid recovery within 3 weeks after cell infusion. Gene correction frequencies in the study cell products averaged >80%. Follow-up data at 6 months in the first patient showed robust levels of gene correction in myeloid (70%), B (94%), NK (100%), and, surprisingly, in his T cell compartment (65%) as well, with a corresponding decline in donor T cell chimerism (99% at baseline, 47% at 6 months). Monitoring of the other treated patients is ongoing. We conclude from our preliminary data that gene therapy using BE HSPCs appear very promising for achieving an earlier and more robust multi-lineage immune reconstitution in adult patients using BE HSPCs.
2026-06-30 | Combined immune deficiency caused by a hypomorphic <i>IL2RG</i> variant and disguised as Burkitt leukemia: a clinical case
X-linked severe combined immunodeficiency (X-SCID) is an inborn error of immunity characterized by almost total absence of T and NK cells with normal counts of functionally impaired B cells (T–B+NK–) that is caused by pathogenic variants in the IL2RG gene resulting in early onset of life-threatening infections. Hypomorphic X-SCIDs present with variable clinical features and are characterized by later onset of infectious complications, a wide range of autoimmune manifestations, and increased risk of malignancies. In this article, we report a rare case of atypical X-SCID presenting with partial red cell aplasia and Burkitt leukemia as the first signs of immune dysregulation. Verification of the diagnosis of X-SCID leads to a different treatment approach, including the use of hematopoetic stem cell transplantation as a curative option. It highlights the importance of awareness of inborn errors of immunity among hematologists and oncologists.
2026-06-01 | Gene Therapy As A Treatment Modality For Severe Combined Immunodeficiency : A Narrative Review
Introduction: Severe combined immunodeficiency (SCID) is a life-threatening genetic disorder marked by severe T-cell defects and often B-cell and NK-cell dysfunction, leading to an increased risk of infections. Treated via gene therapy which is the introduction of modified therapeutic genes either ex vivo or in vivo as a DNA segments. Methods: A Narrative review was conducted followed. Literature was searched on MidLine, pubmed central (PMC), Web of science, Elcevier, Scopus using the following keywords: Severe combined immunodeficiency(SCID), gene therapy and genetic disorders between 2015 and 2024. The included papers were case reports and series, cohort studies, case control and randomized controlled trials. Results: The reviewed literature illustrate that gene therapy has reached significant progress in treating (SCID), particularly X-linked SCID (SCID-X1) and ADA-SCID. Viral vectors especially retroviral, lentiviral, and adeno-associated viral (AAV) vectors have been successfully used to recover T-cell immunity and correct genetic defects, with ADA-SCID patients showing stable immune function and reduced adoption on enzyme replacement therapy. The Protection of lentivirus and foamy virus vectors have been improved, reducing dangers like insertional mutagenesis. Despite their biosafety enhancement, non-viral delivery methods are still limited by their lower transfection efficiency. Conclusion: gene therapy has the ability to treat numerous different primary immunodeficiency (PIDs). There are some limits. Important elements to consider are vector and envelope type, transduction technique, cell dose, delivery modality, conditioning regimen, and illness features. Further research is needed.
2026-05-25 | Modeling and correction of SCID-X1 using CRISPR-Cas9 homology-directed repair in human HSPCs.
X-linked severe combined immunodeficiency (SCID-X1) is a severe primary immunodeficiency caused by mutations in the IL2RG gene, a shared subunit of cytokine receptors critical for the development and function of T and natural killer (NK) cells. The standard treatment, allogeneic hematopoietic stem cell transplantation (HSCT), requires a compatible donor and is often associated with significant transplant-related complications. We aimed to develop a more robust and universal gene therapy by ex vivo modification of patient hematopoietic stem and progenitor cells (HSPCs) using the CRISPR-Cas9/rAAV6 gene-editing platform. To evaluate efficiency, we utilized a feeder-free, in vitro platform enabling T and NK cell differentiation from modified HSPCs. We investigated two approaches: the cut-site method (inserting a corrective cassette downstream of the start codon within the IL2RG locus) and a replacement method (replacing the entire IL2RG gene under endogenous regulation). We demonstrated that the cut-site insertion strategy is preferable for SCID-X1 correction, achieving superior homology-directed repair rates, lower toxicity, and significantly improved T and NK cell differentiation, based on phenotypic marker expression. Importantly, corrected patient-derived HSPCs from two SCID-X1 patients, modified using the cut-site approach, successfully demonstrated phenotypic evidence of T cell differentiation. Therefore, our findings firmly establish the feasibility of the cut-site strategy as a universal, high-efficiency, therapeutic solution for SCID-X1.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
2 orphan drug designations for T-B+ severe combined immunodeficiency due to gamma chain deficiency.
2 orphan drug designations for T-B+ severe combined immunodeficiency due to gamma chain deficiency.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
autologous CD34+ bone marrow derived stem cells transduced with a self-inactivating gammaretroviral vector encoding the human IL2RG (yc) | gene therapies | FDA | 2015-01-15 | — | Boston Children's Hospital |
retroviral gamma-c cDNA containing vector | gene therapies | FDA | 2002-04-29 | — | AVAX technologies, Inc. |
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