RARE DISEASE
Combined immunodeficiency due to partial RAG1 deficiency
Combined immunodeficiency due to partial RAG1 deficiency
Combined immunodeficiency due to partial RAG1 deficiency
Synonyms: CID due to partial RAG1 deficiency, CID with expansion of gamma delta T cells, Combined immunodeficiency with expansion of gamma delta T cells
Synonyms: CID due to partial RAG1 deficiency, CID with expansion of gamma delta T cells, Combined immunodeficiency with expansion of gamma delta T cells
Synonyms: CID due to partial RAG1 deficiency, CID with expansion of gamma delta T cells, Combined immunodeficiency with expansion of gamma delta T cells
Drug discovery
1
drug
With orphan designation
Overview
Combined immunodeficiency due to partial RAG1 deficiency is an autosomal recessive disorder caused by hypomorphic RAG1 mutations, leading to impaired V(D)J recombination. This results in oligoclonal γδ T-cell expansion, αβ T-cell lymphopenia, and variable B-cell dysfunction. Clinical hallmarks include severe cytomegalovirus (CMV) infections, autoimmune cytopenias (e.g., hemolytic anemia), and recurrent bacterial/viral infections. Onset typically occurs in infancy, though delayed presentations with autoimmunity or granulomas are reported. Management combines antimicrobial prophylaxis, immunoglobulin replacement, immunosuppression, and hematopoietic stem cell transplantation (HSCT) for definitive treatment [1][4][6][14].
Burden
High morbidity from chronic infections (CMV, EBV), refractory autoimmunity, and granulomatous organ damage [5][14].
Mortality increases with delayed diagnosis or HSCT; post-transplant survival ranges 54–67%, influenced by active infections or organ damage [3][14].
Lifelong supportive care and treatment complications contribute to significant healthcare utilization [1][5][14].
Therapies
Immunoglobulin replacement, antibiotic/antiviral prophylaxis, and immunosuppressants (e.g., steroids, rituximab) for autoimmunity [1][5].
HSCT with reduced-intensity conditioning for immune reconstitution; survival improves with early transplantation [3][14].
Investigational therapies: Gene editing (CRISPR/Cas9) and viral gene addition for patients lacking HSCT donors [8][13].
Categories: rare genetic diseases, rare immunological diseases, rare transplant-related disorders
Research Papers
24 drug discovery papers about Combined immunodeficiency due to partial RAG1 deficiency, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
24 drug discovery papers about Combined immunodeficiency due to partial RAG1 deficiency, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
cell therapies
2020-09-29 | Asymptomatic Infant With Atypical SCID and Novel Hypomorphic RAG Variant Identified by Newborn Screening: A Diagnostic and Treatment Dilemma
The T-cell receptor excision circle (TREC) assay was designed to detect T-cell lymphopenia (TCL) in newborns, especially to identify severe combined immunodeficiency (SCID). A spectrum of SCID variants and non-SCID conditions that present with TCL are being discovered by SCID newborn screening (NBS) with increasing frequency. Decisions for treatment are influenced by underlying genetic abnormalities. Recombination-activating gene (RAG) deficiency is one the most common causes of classical and atypical SCID and other conditions with immune dysregulation. This case report aims to highlight how NBS can expedite identification of an asymptomatic newborn with a novel hypomorphic RAG variant and a controversial immune phenotype that required in depth immune evaluation to confirm that the abnormal RAG genotype is linked to the disease and justify definitive therapy with hematopoietic stem cell transplantation (HSCT). Following identification of newborns with out of range TREC levels, the diagnostic approach followed at our center includes lymphocyte subset enumeration by flow-cytometry, quantitative serum immunoglobulin levels, lymphocyte proliferation upon mitogen stimulation and next generation DNA sequencing to search for genetic variants associated with SCID. For babies in whom novel RAG gene variants are detected, we also test for immune biomarkers, and if feasible, analyze the recombinase activity of the novel RAG variants by functional assays and T and B-cell receptor repertoire. We identified and validated pathogenicity for compound heterozygous hypomorphic RAG1 variants in an asymptomatic newborn with undetectable TRECs and controversial immunological phenotype with severe TCL, but normal B cell count and lymphocyte proliferation upon mitogen stimulation. Due to the potential for severe complications with infection and immune dysregulation, the patient underwent a matched unrelated HSCT and is doing well 15 months post-HSCT. In conclusion, partial RAG deficiency can be detected by NBS in some cases such as ours. In case of an atypical immune phenotype and novel RAG gene variants, in vivo and in vitro studies are needed to confirm causative association and expedite treatment with HSCT due to risk of serious infection and non-infectious complications.
2020-06-13 | Preclinical Development of Autologous Hematopoietic Stem Cell-Based Gene Therapy for Immune Deficiencies: A Journey from Mouse Cage to Bed Side
Recent clinical trials using patient's own corrected hematopoietic stem cells (HSCs), such as for primary immunodeficiencies (Adenosine deaminase (ADA) deficiency, X-linked Severe Combined Immunodeficiency (SCID), X-linked chronic granulomatous disease (CGD), Wiskott-Aldrich Syndrome (WAS)), have yielded promising results in the clinic; endorsing gene therapy to become standard therapy for a number of diseases. However, the journey to achieve such a successful therapy is not easy, and several challenges have to be overcome. In this review, we will address several different challenges in the development of gene therapy for immune deficiencies using our own experience with Recombinase-activating gene 1 (RAG1) SCID as an example. We will discuss product development (targeting of the therapeutic cells and choice of a suitable vector and delivery method), the proof-of-concept (in vitro and in vivo efficacy, toxicology, and safety), and the final release steps to the clinic (scaling up, good manufacturing practice (GMP) procedures/protocols and regulatory hurdles).
2020-01-19 | Unleashing the cure: Overcoming persistent obstacles in the translation and expanded use of hematopoietic stem cell-based therapies
Abstract Hematopoietic stem cell transplantation (HSCT) is broadly used for treating and curing hematological cancers and various disorders of the blood and immune system. However, its true therapeutic potential remains vastly constrained by significant scientific and technical hurdles that preclude expansion to new indications and limit the number of patients who could benefit from, gain access to, or financially afford the procedure. To define and overcome these challenges, the California Institute for Regenerative Medicine (CIRM) held multiple workshops related to HSCT and has subsequently invested in a new generation of approaches to address the most compelling needs of the field, including new sources of healthy and immunologically compatible hematopoietic stem cells for transplant; safe and efficient genome modification technologies for correction of inherited genetic defects and other forms of gene therapy; safer and more tractable transplantation procedures such as nongenotoxic conditioning regimens, methods to accelerate immune reconstitution and recovery of immune function, and innovations to minimize the risk of immune rejection; and other life-threatening complications from transplant. This Perspective serves to highlight these needs through examples from the recent CIRM-funded and other notable investigations, presents rationale for comprehensive, systematic, and focused strategies to unleash the full potential of HSCT, thereby enabling cures for a greatly expanded number of disorders and making HSCT feasible, accessible, and affordable to all who could benefit. Significance statement Hematopoietic stem cell transplantation (HSCT) is commonly used to treat leukemias and severe disorders of the blood and immune system, but it has not been possible to extend HSCT to many patients in need of transplant, or into various new areas of disease that might benefit. This vast, untapped potential results from inadequate sources of healthy, immune-compatible stem cells for transplant, technological barriers to efficient engraftment, and the significant health risks associated with the HSCT procedure itself. This Perspective elaborates on current limitations of HSCT and describes novel strategies to overcome them, including key innovations developed with support from the California Institute for Regenerative Medicine. Addressing these challenges could greatly expand the feasibility and accessibility of HSCT to all who might benefit, and enable HSCT to serve as a leading paradigm for developing new stem cell-based therapies in the future.
2019-01-12 | Strategies to Improve Posttransplant Immunity
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a well-established curative approach for a variety of malignant and nonmalignant hematologic disorders. However, several complications can occur that lead to transplant failure including progression or recurrence of primary disease, graft-versus-host disease, infection, and regimen-related toxicity. The timing and quality of immune (and in particular T cell) reconstitution can significantly influence many of these complications and thus can have a profound impact on morbidity and mortality following allo-HSCT. In this chapter, we will discuss the well-known causes for this deficiency and then direct our attention to the considerable progress in the development of strategies to enhance T-cell recovery after allo-HSCT.
2018-07-25 | RAG Deficiency: Two Genes, Many Diseases
To review the clinical and laboratory spectrum of RAG gene defects in humans, and discuss the mechanisms underlying phenotypic heterogeneity, the basis of immune dysregulation, and the current and perspective treatment modalities.Literature review and analysis of medical records RESULTS: RAG gene defects in humans are associated with a surprisingly broad spectrum of clinical and immunological phenotypes. Correlation between in vitro recombination activity of the mutant RAG proteins and the clinical phenotype has been observed. Altered T and B cell development in this disease is associated with defects of immune tolerance. Hematopoietic cell transplantation is the treatment of choice for the most severe forms of the disease, but a high rate of graft failure has been observed.Phenotypic heterogeneity of RAG gene defects in humans may represent a diagnostic challenge. There is a need to improve treatment for severe, early-onset forms of the disease. Optimal treatment modalities for patients with delayed-onset disease presenting with autoimmunity and/or inflammation remain to be defined.
cell therapies
2020-09-29 | Asymptomatic Infant With Atypical SCID and Novel Hypomorphic RAG Variant Identified by Newborn Screening: A Diagnostic and Treatment Dilemma
The T-cell receptor excision circle (TREC) assay was designed to detect T-cell lymphopenia (TCL) in newborns, especially to identify severe combined immunodeficiency (SCID). A spectrum of SCID variants and non-SCID conditions that present with TCL are being discovered by SCID newborn screening (NBS) with increasing frequency. Decisions for treatment are influenced by underlying genetic abnormalities. Recombination-activating gene (RAG) deficiency is one the most common causes of classical and atypical SCID and other conditions with immune dysregulation. This case report aims to highlight how NBS can expedite identification of an asymptomatic newborn with a novel hypomorphic RAG variant and a controversial immune phenotype that required in depth immune evaluation to confirm that the abnormal RAG genotype is linked to the disease and justify definitive therapy with hematopoietic stem cell transplantation (HSCT). Following identification of newborns with out of range TREC levels, the diagnostic approach followed at our center includes lymphocyte subset enumeration by flow-cytometry, quantitative serum immunoglobulin levels, lymphocyte proliferation upon mitogen stimulation and next generation DNA sequencing to search for genetic variants associated with SCID. For babies in whom novel RAG gene variants are detected, we also test for immune biomarkers, and if feasible, analyze the recombinase activity of the novel RAG variants by functional assays and T and B-cell receptor repertoire. We identified and validated pathogenicity for compound heterozygous hypomorphic RAG1 variants in an asymptomatic newborn with undetectable TRECs and controversial immunological phenotype with severe TCL, but normal B cell count and lymphocyte proliferation upon mitogen stimulation. Due to the potential for severe complications with infection and immune dysregulation, the patient underwent a matched unrelated HSCT and is doing well 15 months post-HSCT. In conclusion, partial RAG deficiency can be detected by NBS in some cases such as ours. In case of an atypical immune phenotype and novel RAG gene variants, in vivo and in vitro studies are needed to confirm causative association and expedite treatment with HSCT due to risk of serious infection and non-infectious complications.
2020-06-13 | Preclinical Development of Autologous Hematopoietic Stem Cell-Based Gene Therapy for Immune Deficiencies: A Journey from Mouse Cage to Bed Side
Recent clinical trials using patient's own corrected hematopoietic stem cells (HSCs), such as for primary immunodeficiencies (Adenosine deaminase (ADA) deficiency, X-linked Severe Combined Immunodeficiency (SCID), X-linked chronic granulomatous disease (CGD), Wiskott-Aldrich Syndrome (WAS)), have yielded promising results in the clinic; endorsing gene therapy to become standard therapy for a number of diseases. However, the journey to achieve such a successful therapy is not easy, and several challenges have to be overcome. In this review, we will address several different challenges in the development of gene therapy for immune deficiencies using our own experience with Recombinase-activating gene 1 (RAG1) SCID as an example. We will discuss product development (targeting of the therapeutic cells and choice of a suitable vector and delivery method), the proof-of-concept (in vitro and in vivo efficacy, toxicology, and safety), and the final release steps to the clinic (scaling up, good manufacturing practice (GMP) procedures/protocols and regulatory hurdles).
2020-01-19 | Unleashing the cure: Overcoming persistent obstacles in the translation and expanded use of hematopoietic stem cell-based therapies
Abstract Hematopoietic stem cell transplantation (HSCT) is broadly used for treating and curing hematological cancers and various disorders of the blood and immune system. However, its true therapeutic potential remains vastly constrained by significant scientific and technical hurdles that preclude expansion to new indications and limit the number of patients who could benefit from, gain access to, or financially afford the procedure. To define and overcome these challenges, the California Institute for Regenerative Medicine (CIRM) held multiple workshops related to HSCT and has subsequently invested in a new generation of approaches to address the most compelling needs of the field, including new sources of healthy and immunologically compatible hematopoietic stem cells for transplant; safe and efficient genome modification technologies for correction of inherited genetic defects and other forms of gene therapy; safer and more tractable transplantation procedures such as nongenotoxic conditioning regimens, methods to accelerate immune reconstitution and recovery of immune function, and innovations to minimize the risk of immune rejection; and other life-threatening complications from transplant. This Perspective serves to highlight these needs through examples from the recent CIRM-funded and other notable investigations, presents rationale for comprehensive, systematic, and focused strategies to unleash the full potential of HSCT, thereby enabling cures for a greatly expanded number of disorders and making HSCT feasible, accessible, and affordable to all who could benefit. Significance statement Hematopoietic stem cell transplantation (HSCT) is commonly used to treat leukemias and severe disorders of the blood and immune system, but it has not been possible to extend HSCT to many patients in need of transplant, or into various new areas of disease that might benefit. This vast, untapped potential results from inadequate sources of healthy, immune-compatible stem cells for transplant, technological barriers to efficient engraftment, and the significant health risks associated with the HSCT procedure itself. This Perspective elaborates on current limitations of HSCT and describes novel strategies to overcome them, including key innovations developed with support from the California Institute for Regenerative Medicine. Addressing these challenges could greatly expand the feasibility and accessibility of HSCT to all who might benefit, and enable HSCT to serve as a leading paradigm for developing new stem cell-based therapies in the future.
2019-01-12 | Strategies to Improve Posttransplant Immunity
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a well-established curative approach for a variety of malignant and nonmalignant hematologic disorders. However, several complications can occur that lead to transplant failure including progression or recurrence of primary disease, graft-versus-host disease, infection, and regimen-related toxicity. The timing and quality of immune (and in particular T cell) reconstitution can significantly influence many of these complications and thus can have a profound impact on morbidity and mortality following allo-HSCT. In this chapter, we will discuss the well-known causes for this deficiency and then direct our attention to the considerable progress in the development of strategies to enhance T-cell recovery after allo-HSCT.
2018-07-25 | RAG Deficiency: Two Genes, Many Diseases
To review the clinical and laboratory spectrum of RAG gene defects in humans, and discuss the mechanisms underlying phenotypic heterogeneity, the basis of immune dysregulation, and the current and perspective treatment modalities.Literature review and analysis of medical records RESULTS: RAG gene defects in humans are associated with a surprisingly broad spectrum of clinical and immunological phenotypes. Correlation between in vitro recombination activity of the mutant RAG proteins and the clinical phenotype has been observed. Altered T and B cell development in this disease is associated with defects of immune tolerance. Hematopoietic cell transplantation is the treatment of choice for the most severe forms of the disease, but a high rate of graft failure has been observed.Phenotypic heterogeneity of RAG gene defects in humans may represent a diagnostic challenge. There is a need to improve treatment for severe, early-onset forms of the disease. Optimal treatment modalities for patients with delayed-onset disease presenting with autoimmunity and/or inflammation remain to be defined.
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
1 orphan drug designation for Combined immunodeficiency due to partial RAG1 deficiency.
1 orphan drug designation for Combined immunodeficiency due to partial RAG1 deficiency.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Autologous CD34+ cells transduced with a lentiviral vector containing the human RAG1 gene | gene therapies | EMA | 2024-05-24 | — | Leids Universitair Medisch Centrum (LUMC) |
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