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The Journal of Allergy and Clinical... Feb 2023Severe combined immunodeficiency (SCID) results from defects in the differentiation of hematopoietic stem cells into mature T lymphocytes, with additional lymphoid...
Severe combined immunodeficiency (SCID) results from defects in the differentiation of hematopoietic stem cells into mature T lymphocytes, with additional lymphoid lineages affected in particular genotypes. In 2014, the Primary Immune Deficiency Treatment Consortium published criteria for diagnosing SCID, which are now revised to incorporate contemporary approaches. Patients with typical SCID must have less than 0.05 × 10 autologous T cells/L on repetitive testing, with either pathogenic variant(s) in a SCID-associated gene, very low/undetectable T-cell receptor excision circles or less than 20% of CD4 T cells expressing naive markers, and/or transplacental maternally engrafted T cells. Patients with less profoundly impaired autologous T-cell differentiation are designated as having leaky/atypical SCID, with 2 or more of these: low T-cell numbers, oligoclonal T cells, low T-cell receptor excision circles, and less than 20% of CD4 T cells expressing naive markers. These patients must also have either pathogenic variant(s) in a SCID-associated gene or reduced T-cell proliferation to certain mitogens. Omenn syndrome requires a generalized erythematous rash, absent transplacentally acquired maternal engraftment, and 2 or more of these: eosinophilia, elevated IgE, lymphadenopathy, hepatosplenomegaly. Thymic stromal defects and other causes of secondary T-cell deficiency are excluded from the definition of SCID. Application of these revised Primary Immune Deficiency Treatment Consortium 2022 Definitions permits precise categorization of patients with T-cell defects but does not imply a preferred treatment strategy.
Topics: Humans; Severe Combined Immunodeficiency; Immunologic Deficiency Syndromes; CD4-Positive T-Lymphocytes; Thymus Gland; Receptors, Antigen, T-Cell
PubMed: 36456361
DOI: 10.1016/j.jaci.2022.10.022 -
Frontiers in Immunology 2021Inborn errors of immunity (IEI) are a heterogenous group of disorders driven by genetic defects that functionally impact the development and/or function of the innate... (Review)
Review
Inborn errors of immunity (IEI) are a heterogenous group of disorders driven by genetic defects that functionally impact the development and/or function of the innate and/or adaptive immune system. The majority of these disorders are thought to have polygenic background. However, the use of next-generation sequencing in patients with IEI has led to an increasing identification of monogenic causes, unravelling the exact pathophysiology of the disease and allowing the development of more targeted treatments. Monogenic IEI are not only seen in a pediatric population but also in adulthood, either due to the lack of awareness preventing childhood diagnosis or due to a delayed onset where (epi)genetic or environmental factors can play a role. In this review, we discuss the mechanisms accounting for adult-onset presentations and provide an overview of monogenic causes associated with adult-onset IEI.
Topics: Adult; Age of Onset; Autoimmune Diseases; Common Variable Immunodeficiency; Epigenesis, Genetic; Female; Gene-Environment Interaction; Genetic Association Studies; Genetic Predisposition to Disease; Hereditary Autoinflammatory Diseases; High-Throughput Nucleotide Sequencing; Humans; Immunity, Innate; Immunologic Deficiency Syndromes; Lymphohistiocytosis, Hemophagocytic; Lymphoproliferative Disorders; Male; Mosaicism; Mutation; Severe Combined Immunodeficiency
PubMed: 34867986
DOI: 10.3389/fimmu.2021.753978 -
Frontiers in Immunology 2021Gene therapy is an innovative treatment for Primary Immune Deficiencies (PIDs) that uses autologous hematopoietic stem cell transplantation to deliver stem cells with... (Review)
Review
Gene therapy is an innovative treatment for Primary Immune Deficiencies (PIDs) that uses autologous hematopoietic stem cell transplantation to deliver stem cells with added or edited versions of the missing or malfunctioning gene that causes the PID. Initial studies of gene therapy for PIDs in the 1990-2000's used integrating murine gamma-retroviral vectors. While these studies showed clinical efficacy in many cases, especially with the administration of marrow cytoreductive conditioning before cell re-infusion, these vectors caused genotoxicity and development of leukoproliferative disorders in several patients. More recent studies used lentiviral vectors in which the enhancer elements of the long terminal repeats self-inactivate during reverse transcription ("SIN" vectors). These SIN vectors have excellent safety profiles and have not been reported to cause any clinically significant genotoxicity. Gene therapy has successfully treated several PIDs including Adenosine Deaminase Severe Combined Immunodeficiency (SCID), X-linked SCID, Artemis SCID, Wiskott-Aldrich Syndrome, X-linked Chronic Granulomatous Disease and Leukocyte Adhesion Deficiency-I. In all, gene therapy for PIDs has progressed over the recent decades to be equal or better than allogeneic HSCT in terms of efficacy and safety. Further improvements in methods should lead to more consistent and reliable efficacy from gene therapy for a growing list of PIDs.
Topics: Genetic Therapy; Granulomatous Disease, Chronic; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells; Humans; Primary Immunodeficiency Diseases; Severe Combined Immunodeficiency; Treatment Outcome; Wiskott-Aldrich Syndrome; X-Linked Combined Immunodeficiency Diseases
PubMed: 33717203
DOI: 10.3389/fimmu.2021.648951 -
The New England Journal of Medicine May 2021Severe combined immunodeficiency due to adenosine deaminase (ADA) deficiency (ADA-SCID) is a rare and life-threatening primary immunodeficiency.
BACKGROUND
Severe combined immunodeficiency due to adenosine deaminase (ADA) deficiency (ADA-SCID) is a rare and life-threatening primary immunodeficiency.
METHODS
We treated 50 patients with ADA-SCID (30 in the United States and 20 in the United Kingdom) with an investigational gene therapy composed of autologous CD34+ hematopoietic stem and progenitor cells (HSPCs) transduced ex vivo with a self-inactivating lentiviral vector encoding human . Data from the two U.S. studies (in which fresh and cryopreserved formulations were used) at 24 months of follow-up were analyzed alongside data from the U.K. study (in which a fresh formulation was used) at 36 months of follow-up.
RESULTS
Overall survival was 100% in all studies up to 24 and 36 months. Event-free survival (in the absence of reinitiation of enzyme-replacement therapy or rescue allogeneic hematopoietic stem-cell transplantation) was 97% (U.S. studies) and 100% (U.K. study) at 12 months; 97% and 95%, respectively, at 24 months; and 95% (U.K. study) at 36 months. Engraftment of genetically modified HSPCs persisted in 29 of 30 patients in the U.S. studies and in 19 of 20 patients in the U.K. study. Patients had sustained metabolic detoxification and normalization of ADA activity levels. Immune reconstitution was robust, with 90% of the patients in the U.S. studies and 100% of those in the U.K. study discontinuing immunoglobulin-replacement therapy by 24 months and 36 months, respectively. No evidence of monoclonal expansion, leukoproliferative complications, or emergence of replication-competent lentivirus was noted, and no events of autoimmunity or graft-versus-host disease occurred. Most adverse events were of low grade.
CONCLUSIONS
Treatment of ADA-SCID with ex vivo lentiviral HSPC gene therapy resulted in high overall and event-free survival with sustained expression, metabolic correction, and functional immune reconstitution. (Funded by the National Institutes of Health and others; ClinicalTrials.gov numbers, NCT01852071, NCT02999984, and NCT01380990.).
Topics: Adenosine Deaminase; Adolescent; Agammaglobulinemia; Child; Child, Preschool; Genetic Therapy; Genetic Vectors; Hematopoietic Stem Cell Transplantation; Humans; Infant; Lentivirus; Lymphocyte Count; Progression-Free Survival; Prospective Studies; Severe Combined Immunodeficiency; Transplantation, Autologous
PubMed: 33974366
DOI: 10.1056/NEJMoa2027675 -
International Journal of Experimental... Aug 2023Rare diseases collectively exact a high toll on society due to their sheer number and overall prevalence. Their heterogeneity, diversity, and nature pose daunting... (Review)
Review
Rare diseases collectively exact a high toll on society due to their sheer number and overall prevalence. Their heterogeneity, diversity, and nature pose daunting clinical challenges for both management and treatment. In this review, we discuss recent advances in clinical applications of gene therapy for rare diseases, focusing on a variety of viral and non-viral strategies. The use of adeno-associated virus (AAV) vectors is discussed in the context of Luxturna, licenced for the treatment of RPE65 deficiency in the retinal epithelium. Imlygic, a herpes virus vector licenced for the treatment of refractory metastatic melanoma, will be an example of oncolytic vectors developed against rare cancers. Yescarta and Kymriah will showcase the use of retrovirus and lentivirus vectors in the autologous ex vivo production of chimeric antigen receptor T cells (CAR-T), licenced for the treatment of refractory leukaemias and lymphomas. Similar retroviral and lentiviral technology can be applied to autologous haematopoietic stem cells, exemplified by Strimvelis and Zynteglo, licenced treatments for adenosine deaminase-severe combined immunodeficiency (ADA-SCID) and β-thalassaemia respectively. Antisense oligonucleotide technologies will be highlighted through Onpattro and Tegsedi, RNA interference drugs licenced for familial transthyretin (TTR) amyloidosis, and Spinraza, a splice-switching treatment for spinal muscular atrophy (SMA). An initial comparison of the effectiveness of AAV and oligonucleotide therapies in SMA is possible with Zolgensma, an AAV serotype 9 vector, and Spinraza. Through these examples of marketed gene therapies and gene cell therapies, we will discuss the expanding applications of such novel technologies to previously intractable rare diseases.
Topics: Humans; Rare Diseases; Severe Combined Immunodeficiency; Genetic Therapy; Agammaglobulinemia
PubMed: 37177842
DOI: 10.1111/iep.12478 -
The Journal of Experimental Medicine Jan 2020Ex vivo retrovirally mediated gene therapy has been shown within the last 20 yr to correct the T cell immunodeficiency caused by γc-deficiency (SCID X1) and adenosine... (Review)
Review
Ex vivo retrovirally mediated gene therapy has been shown within the last 20 yr to correct the T cell immunodeficiency caused by γc-deficiency (SCID X1) and adenosine deaminase (ADA) deficiency. The rationale was brought up by the observation of the revertant of SCIDX1 and ADA deficiency as a kind of natural gene therapy. Nevertheless, the first attempts of gene therapy for SCID X1 were associated with insertional mutagenesis causing leukemia, because the viral enhancer induced transactivation of oncogenes. Removal of this element and use of a promoter instead led to safer but still efficacious gene therapy. It was observed that a fully diversified T cell repertoire could be generated by a limited set (<1,000) of progenitor cells. Further advances in gene transfer technology, including the use of lentiviral vectors, has led to success in the treatment of Wiskott-Aldrich syndrome, while further applications are pending. Genome editing of the mutated gene may be envisaged as an alternative strategy to treat SCID diseases.
Topics: Adenosine Deaminase; Agammaglobulinemia; Animals; Gene Editing; Gene Transfer Techniques; Genetic Therapy; Genetic Vectors; Humans; Interleukin Receptor Common gamma Subunit; Leukemia; Mutagenesis, Insertional; Mutation, Missense; Retroviridae; Severe Combined Immunodeficiency; T-Lymphocytes; Wiskott-Aldrich Syndrome; X-Linked Combined Immunodeficiency Diseases
PubMed: 31826240
DOI: 10.1084/jem.20190607 -
The New England Journal of Medicine Dec 2022The DNA-repair enzyme Artemis is essential for rearrangement of T- and B-cell receptors. Mutations in , which encodes Artemis, cause Artemis-deficient severe combined...
BACKGROUND
The DNA-repair enzyme Artemis is essential for rearrangement of T- and B-cell receptors. Mutations in , which encodes Artemis, cause Artemis-deficient severe combined immunodeficiency (ART-SCID), which is poorly responsive to allogeneic hematopoietic-cell transplantation.
METHODS
We carried out a phase 1-2 clinical study of the transfusion of autologous CD34+ cells, transfected with a lentiviral vector containing , in 10 infants with newly diagnosed ART-SCID. We followed them for a median of 31.2 months.
RESULTS
Marrow harvest, busulfan conditioning, and lentiviral-transduced CD34+ cell infusion produced the expected grade 3 or 4 adverse events. All the procedures met prespecified criteria for feasibility at 42 days after infusion. Gene-marked T cells were detected at 6 to 16 weeks after infusion in all the patients. Five of 6 patients who were followed for at least 24 months had T-cell immune reconstitution at a median of 12 months. The diversity of T-cell receptor β chains normalized by 6 to 12 months. Four patients who were followed for at least 24 months had sufficient B-cell numbers, IgM concentration, or IgM isohemagglutinin titers to permit discontinuation of IgG infusions. Three of these 4 patients had normal immunization responses, and the fourth has started immunizations. Vector insertion sites showed no evidence of clonal expansion. One patient who presented with cytomegalovirus infection received a second infusion of gene-corrected cells to achieve T-cell immunity sufficient for viral clearance. Autoimmune hemolytic anemia developed in 4 patients 4 to 11 months after infusion; this condition resolved after reconstitution of T-cell immunity. All 10 patients were healthy at the time of this report.
CONCLUSIONS
Infusion of lentiviral gene-corrected autologous CD34+ cells, preceded by pharmacologically targeted low-exposure busulfan, in infants with newly diagnosed ART-SCID resulted in genetically corrected and functional T and B cells. (Funded by the California Institute for Regenerative Medicine and the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number, NCT03538899.).
Topics: Humans; Infant; Busulfan; Genetic Therapy; Immunoglobulin M; Severe Combined Immunodeficiency; DNA Repair Enzymes; Antigens, CD34; Transplantation, Autologous; Lentivirus; Genetic Vectors; T-Lymphocytes; B-Lymphocytes
PubMed: 36546626
DOI: 10.1056/NEJMoa2206575 -
Therapeutics and Clinical Risk... 2022Adenosine deaminase deficiency (ADA) is a purine salvage pathway deficiency that results in buildup of toxic metabolites causing death in rapidly dividing cells,... (Review)
Review
Adenosine deaminase deficiency (ADA) is a purine salvage pathway deficiency that results in buildup of toxic metabolites causing death in rapidly dividing cells, especially lymphocytes. The most complete form of ADA leads to severe combined immune deficiency (SCID). Treatment with enzyme replacement therapy (ERT) was developed in the 1970s and became the treatment for ADA SCID by the 1980s. It remains an option for some infants with SCID, and a stopgap measure for others awaiting curative therapy. For some infants with ADA SCID who have matching family donors hematopoietic stem cell transplant (HSCT) is an option for cure. Gene therapy for ADA SCID, approved in some countries and in trials in others, is becoming possible for more infants with this disorder. This review covers the history of ADA SCID, the treatment options to date and particularly the history of the development of gene therapy for ADA SCID and the current state of the risks and benefits of the gene therapy option.
PubMed: 36172599
DOI: 10.2147/TCRM.S350762 -
Nucleic Acids Research Jul 2022Artemis nuclease and DNA-dependent protein kinase catalytic subunit (DNA-PKcs) are key components in nonhomologous DNA end joining (NHEJ), the major repair mechanism for...
Artemis nuclease and DNA-dependent protein kinase catalytic subunit (DNA-PKcs) are key components in nonhomologous DNA end joining (NHEJ), the major repair mechanism for double-strand DNA breaks. Artemis activation by DNA-PKcs resolves hairpin DNA ends formed during V(D)J recombination. Artemis deficiency disrupts development of adaptive immunity and leads to radiosensitive T- B- severe combined immunodeficiency (RS-SCID). An activated state of Artemis in complex with DNA-PK was solved by cryo-EM recently, which showed Artemis bound to the DNA. Here, we report that the pre-activated form (basal state) of the Artemis:DNA-PKcs complex is stable on an agarose-acrylamide gel system, and suitable for cryo-EM structural analysis. Structures show that the Artemis catalytic domain is dynamically positioned externally to DNA-PKcs prior to ABCDE autophosphorylation and show how both the catalytic and regulatory domains of Artemis interact with the N-HEAT and FAT domains of DNA-PKcs. We define a mutually exclusive binding site for Artemis and XRCC4 on DNA-PKcs and show that an XRCC4 peptide disrupts the Artemis:DNA-PKcs complex. All of the findings are useful in explaining how a hypomorphic L3062R missense mutation of DNA-PKcs could lead to insufficient Artemis activation, hence RS-SCID. Our results provide various target site candidates to design disruptors for Artemis:DNA-PKcs complex formation.
Topics: DNA Repair; DNA-Activated Protein Kinase; DNA-Binding Proteins; Endonucleases; Humans; Nuclear Proteins; Severe Combined Immunodeficiency
PubMed: 35801871
DOI: 10.1093/nar/gkac564