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Eight infants with SCID-X1 had multilineage immune reconstitution after autologous hematopoietic stem-cell transplantation of marrow stem cells transfected with a lentiviral vector containing IL2RG cDNA after busulfan conditioning. Previous infections cleared and functional T cells developed in all eight infants, IgM levels normalized in seven, and three had a response to vaccines.

Correction of the genetic lesion leading to X-linked SCID with first-generation retroviral vectors has been associated with a 25% risk of acute leukemia. A self-inactivating retrovirus appears to retain therapeutic efficacy, with no leukemia yet observed. X-linked severe combined immunodeficiency (SCID-X1) is caused by mutations in the gene encoding the interleukin-2 receptor γ chain ( IL2RG ) that result in a lack of response to common γ-chain (γc)–dependent cytokines, an absence of T-cell and natural killer (NK)–cell development, and impairment of B-cell function. 1 , 2 Death from community-acquired or opportunistic infection usually occurs before 1 year of age unless allogeneic hematopoietic stem-cell transplantation (HSCT) is performed. The immunologic defect in children with SCID-X1 obviates the requirement for a preparative regimen before transplantation. 3 – 6 Standard allogeneic HSCT with matched-sibling donors is associated with an 85 to 90% overall . . .

The interleukin-2 receptor gamma chain gene ( ) encodes for the common γ chain (γ ) protein, that is a shared signaling component of multiple interleukin receptors, including IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21, and plays a pivotal role in lymphocyte development, homeostasis, and function. Mutations in cause X-linked severe combined immunodeficiency (X-SCID) and a broad spectrum of related phenotypes ranging from typical SCID to leaky or atypical presentations, sometimes mimicking common variable immunodeficiency or immune dysregulation syndromes. Over the last decade (2015-2025), advances in molecular diagnostics, next-generation sequencing, and functional immunology have expanded the known mutational spectrum and refined genotype-phenotype correlations. Recent research has uncovered novel hypomorphic variants, revealed the structural basis of receptor dysfunction, and elucidated the impact of specific mutations on JAK-STAT signaling. Longitudinal natural history studies have improved understanding of disease progression in partial loss-of-function cases, while expanded newborn screening for SCID has facilitated earlier diagnosis. Advances in preclinical and clinical gene therapy have addressed historical challenges such as insertional mutagenesis, with emerging protocols achieving stable multilineage immune reconstitution. Moreover, comparative HSCT outcome analyses have informed donor selection, conditioning strategies, and post-transplant care, particularly in resource-limited settings. Improved molecular diagnostics have enabled precision diagnosis in patients with atypical presentations, allowing earlier initiation of curative therapies such as HSCT or gene therapy. Recognition of immune dysregulation, autoimmunity, and malignancy as part of the -related spectrum has refined long-term follow-up protocols. Multidisciplinary care, integrating infectious disease, immunology, and genetics expertise, has become essential for optimizing patient outcomes. Ongoing priorities include the expansion of gene therapy trials to cover hypomorphic and late-presenting cases, refinement of reduced-intensity conditioning regimens to minimize toxicity, and development of targeted molecular therapies to modulate downstream signaling in non-transplant candidates. Global initiatives for SCID newborn screening, coupled with collaborative registries, are expected to improve early diagnosis and equitable access to curative interventions.

Gene correction in human long-term hematopoietic stem cells (LT-HSCs) could be an effective therapy for monogenic diseases of the blood and immune system. Here we describe an approach for X-linked sSevere cCombined iImmunodeficiency (SCID-X1) using targeted integration of a cDNA into the endogenous start codon to functionally correct disease-causing mutations throughout the gene. Using a CRISPR-Cas9/AAV6 based strategy, we achieve up to 20% targeted integration frequencies in LT-HSCs. As measures of the lack of toxicity we observe no evidence of abnormal hematopoiesis following transplantation and no evidence of off-target mutations using a high-fidelity Cas9 as a ribonucleoprotein complex. We achieve high levels of targeting frequencies (median 45%) in CD34 + HSPCs from six SCID-X1 patients and demonstrate rescue of lymphopoietic defect in a patient derived HSPC population in vitro and in vivo. In sum, our study provides specificity, toxicity and efficacy data supportive of clinical development of genome editing to treat SCID-Xl. Gene correction in hematopoietic stem cells could be a powerful way to treat monogenic diseases of the blood and immune system. Here the authors develop a strategy using CRISPR-Cas9 and an aAdeno-Associated vVirus(AAV)-delivered IL2RG cDNA to correct X-linked sSevere Ccombined iImmunodeficiency (SCID-X1) with a high success rate.

X-linked Severe Combined Immunodeficiency (SCID-X1) due to IL2RG mutations is potentially fatal in infancy where ‘emergency’ life-saving stem cell transplant may only achieve incomplete immune reconstitution following transplant. Salvage therapy SCID-X1 patients over 2 years old (NCT01306019) is a non-randomized, open-label, phase I/II clinical trial for administration of lentiviral-transduced autologous hematopoietic stem cells following busulfan (6 mg/kg total) conditioning. The primary and secondary objectives assess efficacy in restoring immunity and safety by vector insertion site analysis (VISA). In this ongoing study (19 patients treated), we report VISA in blood lineages from first eight treated patients with longer follow up found a > 60-fold increase in frequency of forward-orientated VIS within intron 3 of the High Mobility Group AT-hook 2 gene. All eight patients demonstrated emergence of dominant HMGA2 VIS clones in progenitor and myeloid lineages, but without disturbance of hematopoiesis. Our molecular analysis demonstrated a cryptic splice site within the chicken β-globin hypersensitivity 4 insulator element in the vector generating truncated mRNA transcripts from many transcriptionally active gene containing forward-oriented intronic vector insert. A two base-pair change at the splice site within the lentiviral vector eliminated splicing activity while retaining vector functional capability. This highlights the importance of functional analysis of lentivectors for cryptic splicing for preclinical safety assessment and a redesign of clinical vectors to improve safety. De Ravin et al. report an unplanned interim analysis of a secondary safety outcome for an ongoing clinical trial on lentiviral gene therapy for the treatment of X-linked Severe Combined Immunodeficiency (NCT01306019). Vector induced alternative splicing events are identified that cause aberrant fusion transcripts, leading to clonal dominance in a single patient and clonal expansion in others. This can be mitigated by the removal of the lentivector cryptic splice acceptor.

gene therapy for treatment of Inborn errors of Immunity (IEIs) have demonstrated significant clinical benefit in multiple Phase I/II clinical trials. Current approaches rely on engineered retroviral vectors to randomly integrate copy(s) of gene-of-interest in autologous hematopoietic stem/progenitor cells (HSPCs) genome permanently to provide gene function in transduced HSPCs and their progenies. To circumvent concerns related to potential genotoxicities due to the random vector integrations in HSPCs, targeted correction with CRISPR-Cas9-based genome editing offers improved precision for functional correction of multiple IEIs. We compare the two approaches for integration of transgene for functional correction of HSPCs from patients with X-linked Severe Combined Immunodeficiency (SCID-X1 or XSCID); delivery current clinical lentivector (LV)- versus targeted insertion (TI) of homology-directed repair (HDR) when using an adeno-associated virus (AAV)- donor following double-strand DNA break at the endogenous locus. differentiation of LV- or TI-treated XSCID HSPCs similarly overcome differentiation block into Pre-T-I and Pre-T-II lymphocytes but we observed significantly superior development of NK cells when corrected by TI (40.7% versus 4.1%, p = 0.0099). Transplants into immunodeficient mice demonstrated robust engraftment (8.1% and 23.3% in bone marrow) for LV- and TI- HSPCs with efficient T cell development following TI- in all four patients' HSPCs. Extensive specificity analysis of CRISPR-Cas9 editing with rhAmpSeq covering 82 predicted off-target sites found no evidence of indels in edited cells before ( ) or following transplant, in stark contrast to LV's non-targeted vector integration sites. Together, the improved efficiency and safety of correction CRISPR-Cas9-based TI approach provides a strong rationale for a clinical trial for treatment of XSCID patients.

XMEN disease (X-linked immunodeficiency with magnesium defect, EBV infection, and neoplasia) is a rare Inborn Error of Immunity (IEI)characterized by impaired magnesium ion transport due to mutations in the MAGT1 gene, which subsequently affects immune cell function. Timely diagnosis and prompt intervention are essential for improving patient outcomes. Allogeneic hematopoietic stem cell transplantation (HSCT) offers a potential therapeutic approach to restore MAGT1 function. We report an infant with XMEN who acquired a novel mutation in the MAGT1 gene, presenting recurrent severe skin infections and neutropenia after 6 months of age, which was effectively managed following aggressive anti-infective treatment and HSCT.

X-linked severe combined immunodeficiency (X-SCID), caused by mutations in the gamma-chain gene of the interleukin-2 receptor (IL2RG), is a prevalent form of SCID characterized by recurrent and fatal opportunistic infections that occur early in life. The incidence of disseminated bacillus Calmette-Guérin (BCG) disease among children with SCID is much higher than in the general population. Here, we report the case of a 4-month-old male infant who presented with subcutaneous induration, fever, an unhealed BCG vaccination site, and hepatosplenomegaly. Metagenomic next-generation sequencing in blood, and the detection of gastric juice and skin nodule pus all confirmed the infection of Mycobacterium tuberculosis . Lymphocyte subset analysis confirmed the presence of T-B+NK immunodeficiency. Whole-exome and Sanger sequencing revealed a novel microdeletion insertion mutation (c.316_318delinsGTGAT p.Leu106ValfsTer42) in the IL2RG gene, resulting in a rare shift in the amino acid sequence of the coding protein. Consequently, the child was diagnosed with X-SCID caused by a novel mutation in IL2RG, complicated by systemic disseminated BCG disease. Despite receiving systemic anti-infection treatment and four days of hospitalization, the patient died three days after discharge. To the best of our knowledge, this specific IL2RG mutation has not been previously reported. In our systemic review, we outline the efficacy of systemic anti-tuberculosis therapy, hematopoietic stem cell transplantation, and gene therapy in children with SCID and BCG diseases caused by IL2RG gene mutation.

Recent reports have challenged the notion that retroviruses and retroviral vectors integrate randomly into the host genome. These reports pointed to a strong bias toward integration in and near gene coding regions and, for gammaretroviral vectors, around transcription start sites. Here, we report the results obtained from a large-scale mapping of 572 retroviral integration sites (RISs) isolated from cells of 9 patients with X-linked SCID (SCID-X1) treated with a retrovirus-based gene therapy protocol. Our data showed that two-thirds of insertions occurred in or very near to genes, of which more than half were highly expressed in CD34(+) progenitor cells. Strikingly, one-fourth of all integrations were clustered as common integration sites (CISs). The highly significant incidence of CISs in circulating T cells and the nature of their locations indicate that insertion in many gene loci has an influence on cell engraftment, survival, and proliferation. Beyond the observed cases of insertional mutagenesis in 3 patients, these data help to elucidate the relationship between vector insertion and long-term in vivo selection of transduced cells in human patients with SCID-X1.