-
Orphanet Journal of Rare Diseases Apr 2018Adenosine deaminase (ADA) deficiency leads to an accumulation of toxic purine degradation by-products, most potently affecting lymphocytes, leading to adenosine... (Review)
Review
Adenosine deaminase (ADA) deficiency leads to an accumulation of toxic purine degradation by-products, most potently affecting lymphocytes, leading to adenosine deaminase-deficient severe combined immunodeficiency. Whilst most notable affects are on lymphocytes, other manifestations include skeletal abnormalities, neurodevelopmental affects and pulmonary manifestations associated with pulmonary-alveolar proteinosis. Affected patients present in early infancy, usually with persistent infection, or with pulmonary insufficiency. Three treatment options are currently available. Initial treatment with enzyme replacement therapy may alleviate acute symptoms and enable partial immunological reconstitution, but treatment is life-long, immune reconstitution is incomplete, and the reconstituted immune system may nullify the effects of the enzyme replacement. Hematopoietic stem cell transplant has long been established as the treatment of choice, particularly where a matched sibling or well matched unrelated donor is available. More recently, the use of gene addition techniques to correct the genetic defect in autologous haematopoietic stem cells treatment has demonstrated immunological and clinical efficacy. This article reviews the biology, clinical presentation, diagnosis and treatment of ADA-deficiency.
Topics: Adenosine Deaminase; Agammaglobulinemia; Female; Hematopoietic Stem Cell Transplantation; Humans; Male; Pulmonary Alveolar Proteinosis; Severe Combined Immunodeficiency
PubMed: 29690908
DOI: 10.1186/s13023-018-0807-5 -
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 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 -
Cell Mar 2023CD3δ SCID is a devastating inborn error of immunity caused by mutations in CD3D, encoding the invariant CD3δ chain of the CD3/TCR complex necessary for normal...
CD3δ SCID is a devastating inborn error of immunity caused by mutations in CD3D, encoding the invariant CD3δ chain of the CD3/TCR complex necessary for normal thymopoiesis. We demonstrate an adenine base editing (ABE) strategy to restore CD3δ in autologous hematopoietic stem and progenitor cells (HSPCs). Delivery of mRNA encoding a laboratory-evolved ABE and guide RNA into a CD3δ SCID patient's HSPCs resulted in a 71.2% ± 7.85% (n = 3) correction of the pathogenic mutation. Edited HSPCs differentiated in artificial thymic organoids produced mature T cells exhibiting diverse TCR repertoires and TCR-dependent functions. Edited human HSPCs transplanted into immunodeficient mice showed 88% reversion of the CD3D defect in human CD34+ cells isolated from mouse bone marrow after 16 weeks, indicating correction of long-term repopulating HSCs. These findings demonstrate the preclinical efficacy of ABE in HSPCs for the treatment of CD3δ SCID, providing a foundation for the development of a one-time treatment for CD3δ SCID patients.
Topics: Humans; Animals; Mice; T-Lymphocytes; Severe Combined Immunodeficiency; Gene Editing; Mice, SCID; CD3 Complex; Receptors, Antigen, T-Cell
PubMed: 36944331
DOI: 10.1016/j.cell.2023.02.027 -
Nihon Rinsho Men'eki Gakkai Kaishi =... 2017Mutations in the RAG1/RAG2 genes are associated with a broad spectrum of clinical phenotypes, ranging from severe combined immunodeficiency to various autoimmune... (Review)
Review
Mutations in the RAG1/RAG2 genes are associated with a broad spectrum of clinical phenotypes, ranging from severe combined immunodeficiency to various autoimmune diseases. The diversity of the clinical symptoms is determined not only by the residual RAG recombinase enzyme activity as determined by the mutations, but also by multiple environmental factors and, in rare cases, by second site mutations within the RAG1/RAG2 genes. The residual recombinase activity is responsible for the oligoclonal expansion of autoreactive T cells. Omenn syndrome is the result of intense Th2 type inflammation involving the skin and multiple other organs triggered by these T cells. In this review, the molecular pathology of diseases caused by RAG1/RAG2 mutations, in particular Omenn syndrome, will be discussed. Furthermore, abnormalities in other molecules involved in V(D)J recombination will be discussed in relation to Omenn-like syndrome.
Topics: DNA; DNA-Binding Proteins; Genetic Association Studies; Homeodomain Proteins; Humans; Mutation; Nuclear Proteins; Severe Combined Immunodeficiency; Th2 Cells; V(D)J Recombination
PubMed: 28747605
DOI: 10.2177/jsci.40.179 -
F1000Research 2019Recombination-activating genes ( ) and initiate the molecular processes that lead to lymphocyte receptor formation through VDJ recombination. Nonsense mutations in /... (Review)
Review
Recombination-activating genes ( ) and initiate the molecular processes that lead to lymphocyte receptor formation through VDJ recombination. Nonsense mutations in / cause the most profound immunodeficiency syndrome, severe combined immunodeficiency (SCID). Other severe and less-severe clinical phenotypes due to mutations in genes are now recognized. The degree of residual protein function may permit some lymphocyte receptor formation, which confers a less-severe clinical phenotype. Many of the non-SCID phenotypes are associated with autoimmunity. New findings into the effect of mutations in on the developing T- and B-lymphocyte receptor give insight into the development of autoimmunity. This article summarizes recent findings and places the genetic and molecular findings in a clinical context.
Topics: Animals; Autoimmunity; DNA-Binding Proteins; Homeodomain Proteins; Humans; Nuclear Proteins; Receptors, Antigen, B-Cell; Receptors, Antigen, T-Cell; Severe Combined Immunodeficiency
PubMed: 30800289
DOI: 10.12688/f1000research.17056.1 -
Current Opinion in Immunology Feb 2023Increased immunogloblulin-E (IgE) levels associated with eosinophilia represent a common finding observed in Omenn syndrome, a severe immunodeficiency caused by... (Review)
Review
Increased immunogloblulin-E (IgE) levels associated with eosinophilia represent a common finding observed in Omenn syndrome, a severe immunodeficiency caused by decreased V(D)J recombination, leading to restricted T- and B-cell receptor repertoire. V(D)J recombination is initiated by the lymphoid-restricted recombination-activating gene (RAG) recombinases. The lack of RAG proteins causes a block in lymphocyte differentiation, resulting in TB severe combined immunodeficiency. Conversely, hypomorphic mutations allow the generation of few T and B cells, leading to a spectrum of immunological phenotypes, in which immunodeficiency associates to inflammation, immune dysregulation, and autoimmunity. Elevated IgE levels are frequently observed in hypomorphic RAG patients. Here, we describe the role of RAG genes in lymphocyte differentiation and maintenance of immune tolerance.
Topics: Humans; DNA-Binding Proteins; Immunologic Deficiency Syndromes; Severe Combined Immunodeficiency; Mutation; Immunoglobulin E
PubMed: 36529093
DOI: 10.1016/j.coi.2022.102279 -
Journal of the European Academy of... Jul 2022The broad differential diagnosis of neonatal erythroderma often poses a diagnostic challenge. Mortality of neonatal erythroderma is high due to complications of the... (Review)
Review
The broad differential diagnosis of neonatal erythroderma often poses a diagnostic challenge. Mortality of neonatal erythroderma is high due to complications of the erythroderma itself and the occasionally severe and life-threatening underlying disease. Early correct recognition of the underlying cause leads to better treatment and prognosis. Currently, neonatal erythroderma is approached on a case-by-case basis. The purpose of this scoping review was to develop a diagnostic approach in neonatal erythroderma. After a systematic literature search in Embase (January 1990 - May 2020, 74 cases of neonatal erythroderma were identified, and 50+ diagnoses could be extracted. Main causes were the ichthyoses (40%) and primary immunodeficiencies (35%). Congenital erythroderma was present in 64% (47/74) of the cases, predominantly with congenital ichthyosis (11/11; 100%), Netherton syndrome (12/14, 86%) and Omenn syndrome (11/23, 48%). Time until diagnosis ranged from 102 days to 116 days for cases of non-congenital erythroderma and congenital erythroderma respectively. Among the 74 identified cases a total of 17 patients (23%) died within a mean of 158 days and were related to Omenn syndrome (35%), graft-versus-host disease (67%) and Netherton syndrome (18%). Disease history and physical examination are summarized in this paper. Age of onset and a collodion membrane can help to narrow the differential diagnoses. Investigations of blood, histology, hair analysis, genetic analysis and clinical imaging are summarized and discussed. A standard blood investigation is proposed, and the need for skin biopsies with lympho-epithelial Kazal-type related Inhibitor staining is highlighted. Overall, this review shows that diagnostic procedures narrow the differential diagnosis in neonatal erythroderma. A 6-step flowchart for the diagnostic approach for neonatal erythroderma during the first month of life is proposed. The approach was made with the support of expert leaders from international multidisciplinary collaborations in the European Reference Network Skin-subthematic group Ichthyosis.
Topics: Dermatitis, Exfoliative; Diagnosis, Differential; Humans; Ichthyosis; Ichthyosis, Lamellar; Infant, Newborn; Netherton Syndrome; Severe Combined Immunodeficiency
PubMed: 35238435
DOI: 10.1111/jdv.18043 -
British Journal of Haematology Jun 2021Primary immunodeficiencies (PIDs) are a group of rare inherited disorders of the immune system. Many PIDs are devastating and require a definitive therapy to prevent... (Review)
Review
Primary immunodeficiencies (PIDs) are a group of rare inherited disorders of the immune system. Many PIDs are devastating and require a definitive therapy to prevent progressive morbidity and premature mortality. Allogeneic haematopoietic stem cell transplantation (alloHSCT) is curative for many PIDs, and while advances have resulted in improved outcomes, the procedure still carries a risk of mortality and morbidity from graft failure or graft-versus-host disease (GvHD). Autologous haematopoietic stem cell gene therapy (HSC GT) has the potential to correct genetic defects across haematopoietic lineages without the complications of an allogeneic approach. HSC GT for PID has been in development for the last two decades and the first licensed HSC-GT product for adenosine deaminase-deficient severe combined immunodeficiency (ADA-SCID) is now available. New gene editing technologies have the potential to circumvent some of the problems associated with viral gene-addition. HSC GT for PID shows great promise, but requires a unique approach for each disease and carries risks, notably insertional mutagenesis from gamma-retroviral gene addition approaches and possible off-target toxicities from gene-editing techniques. In this review, we discuss the development of HSC GT for PID and outline the current state of clinical development before discussing future developments in the field.
Topics: Agammaglobulinemia; Autografts; Gene Editing; Genetic Therapy; Hematopoietic Stem Cell Transplantation; Humans; Severe Combined Immunodeficiency
PubMed: 33336808
DOI: 10.1111/bjh.17269 -
Journal of Clinical Immunology Aug 2018To review the clinical and laboratory spectrum of RAG gene defects in humans, and discuss the mechanisms underlying phenotypic heterogeneity, the basis of immune... (Review)
Review
PURPOSE
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.
METHODS
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.
CONCLUSIONS
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.
Topics: Animals; Autoimmunity; Biological Variation, Population; DNA-Binding Proteins; Genetic Association Studies; Genetic Predisposition to Disease; Homeodomain Proteins; Humans; Immunity; Mutation; Nuclear Proteins; Phenotype; Severe Combined Immunodeficiency
PubMed: 30046960
DOI: 10.1007/s10875-018-0537-4