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BACKGROUND: Inborn errors of immunity (IEI) are rare diseases, which makes diagnosis a challenge. A better description of the initial presenting manifestations should improve awareness and avoid diagnostic delay. Although increased infection susceptibility is a well-known initial IEI manifestation, less is known about the frequency of other presenting manifestations.OBJECTIVE: We sought to analyze age-related initial presenting manifestations of IEI including different IEI disease cohorts.METHODS: We analyzed data on 16,486 patients of the European Society for Immunodeficiencies Registry. Patients with autoinflammatory diseases were excluded because of the limited number registered.RESULTS: Overall, 68% of patients initially presented with infections only, 9% with immune dysregulation only, and 9% with a combination of both. Syndromic features were the presenting feature in 12%, 4% had laboratory abnormalities only, 1.5% were diagnosed because of family history only, and 0.8% presented with malignancy. Two-third of patients with IEI presented before the age of 6 years, but a quarter of patients developed initial symptoms only as adults. Immune dysregulation was most frequently recognized as an initial IEI manifestation between age 6 and 25 years, with male predominance until age 10 years, shifting to female predominance after age 40 years. Infections were most prevalent as a first manifestation in patients presenting after age 30 years.CONCLUSIONS: An exclusive focus on infection-centered warning signs would have missed around 25% of patients with IEI who initially present with other manifestations.

B cells are essential for Ab production during humoral immune responses. From decades of B cell research, there is now a detailed understanding of B cell subsets, development, functions, and most importantly, signaling pathways. The complicated pathways in B cells and their interactions with each other are stage-dependent, varying with surface marker expression during B cell development. With the increasing understanding of B cell development and signaling pathways, the mechanisms underlying B cell related diseases are being unraveled as well, making it possible to provide more precise and effective treatments. In this review, we describe several essential and recently discovered signaling pathways in B cell development and take a look at newly developed therapeutic strategies targeted at B cell signaling.

Background Adenosine deaminase deficiency (ADA) is an autosomal recessive disorder leading to severe combined immunodeficiency (SCID). It is characterized patho-physiologically by intracellular accumulation of toxic products affecting lymphocytes. Other organ systems are known to be affected causing non-immune abnormalities. We aimed to conduct a cross sectional study to describe liver disease in autosomal recessive ADA-SCID. Methods Single center retrospective analysis of genetically confirmed autosomal recessive ADA-SCID was performed. Liver disease was defined as ≥1.5x the gender specific upper limit of normal (ULN; 33 IU/L for males and 25 IU/L for females) alanine aminotransferase (ALT) or moderate and severe increase in liver echogenicity on ultrasound. Results The cohort included 18 patients with 11 males. The median age was 11.5 (3.5–30.0 years) and median BMI percentile was 75.5 [36.75, 89.5]. All patients received enzyme replacement therapy at the time of evaluation. Seven (38%) and five (27%) patients had gene therapy (GT) and hematopoietic stem cell transplant (HSCT) in the past. Five patients had 1.5x ALT level more than 1.5x the U. Liver echogenicity was mild in 6 (33%), moderate in 2 (11%) and severe in 2 (11%) patients. All patients had normal Fibrosis-4 Index and Non-alcoholic fatty liver disease fibrosis biomarker scores indicating absence of advanced fibrosis in our cohort. Of 5 patients who had liver biopsies, steatohepatitis was noted in 3 patients (NAS score of 3,3,4). Discussion Non-immunologic manifestations of ADA-SCID have become more apparent in recent years as survival improved. We concluded that steatosis is the most common finding noted in our ADA-SCID cohort.

Background: X-linked inhibitor of apoptosis (XIAP) deficiency is a rare primary immunodeficiency disease caused by XIAP gene mutations. A broad range of phenotype, severity, and age at onset present challenges for patient management.Objective: We sought to characterize the phenotype, treatment, and survival outcomes of XIAP deficiency and to assess parameters influencing prognosis.Methods: Data published from 2006 to 2020 were retrospectively analyzed.Results: A total of 167 patients from 117 families with XIAP deficiency were reported with 90 different mutations. A wide spectrum of clinical features were seen, of which hemophagocytic lymphohistiocytosis (HLH) and inflammatory bowel disease were the most common. Patients frequently developed multiple features with no clear genotype-phenotype correlation. A total of 117 patients were managed conservatively and 50 underwent hematopoietic stem-cell transplantation (HSCT), with respective overall survival probabilities of 90% and 53% at age 16 years. The predominant indication for HSCT was early-onset HLH. Active HLH and myeloablative conditioning regimens increased HSCT-related mortality, although HSCT outcome was much better after 2015 than before. For conservatively managed patients reaching adulthood, survival probabilities were 86% at age 30 years and 37% by age 52 years, with worse outcomes for patients developing the disease before the age of 5 years or with new disease features in adulthood. Nine asymptomatic mutation carriers with a median age of 13.5 years were identified.Conclusions: Our study demonstrates the variable nature of XIAP deficiency, which evolves over life for individual patients. Better therapeutic strategies and prospective studies are required to reduce morbidity and mortality and improve decision making and long-term outcomes for patients with XIAP deficiency. (J Allergy Clin Immunol 2022;150:456-66.)

Il n’est pas aisé de distinguer le normal de l’inhabituel en ce qui concerne les infections durant les premières années de vie. En effet, le système immunitaire est alors encore en plein développement et l’exposition microbienne est généralement importante, en particulier dans un contexte de garde en collectivité. Le but de cet article est de clarifier les éléments faisant suspecter un déficit immunitaire primaire, de proposer un bilan biologique ainsi que son rationnel et quelques éléments de suivi des patients avec immunodéficience dont le rôle du pédiatre de premier recours doit rester central. Nous n’aborderons pas ici l’immunodéficience secondaire à des traitements ou des infections.

Es ist nicht einfach, im Verlaufe des ersten Lebensjahres, normale Infektionen von ungewöhnlichen zu unterscheiden. Das Immunsystem befindet sich in voller Entwicklung und Kinder sind einer grossen Anzahl Keime ausgesetzt, insbesondere bei kollektiver Betreuung. Ziel dieses Artikels ist es, die Elemente herauszuarbeiten, die an einen primären Immundefekt denken lassen, entsprechende Laborabklärungen vorzuschlagen und zu begründen, sowie einige Punkte hinsichtlich der Betreuung von Patienten mit einem Immundefekt darzulegen, da der Kinderarzt in der Erstversorgung eine zentrale Rolle einnimmt. Auf sekundäre Immundefekte, medikamentösen oder infektiösen Ursprungs, wird hier nicht eingegangen.

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 ADA. 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 ADA expression, metabolic correction, and functional immune reconstitution. (Funded by the National Institutes of Health and others; ClinicalTrials.gov numbers, NCT01852071, NCT02999984, and NCT01380990.)

Four individuals from two families presented with a multisystemic condition of suspected genetic origin that was diagnosed only after genome analysis. The main phenotypic features were immune system dysregulation (severe immunodeficiency with autoimmunity) and intellectual disability. The four individuals were found to be homozygous for a 4.4 Kb deletion removing exons 20 to 23 (NM_003291.4) of the TPP2 gene, predicting a frameshift with premature termination of the protein. The deletion was located on a shared chromosome 13 haplotype indicating a Swiss founder mutation. Tripeptidyl peptidase 2 (TPP2) is a protease involved in HLA/antigen complex processing and amino acid homeostasis. Biallelic variants in TPP2 have been described in ten individuals with variable features including immune deficiency, autoimmune cytopenias, and intellectual disability or chronic sterile brain inflammation mimicking multiple sclerosis. Our observations further delineate this severe condition not yet included in the OMIM catalog. Timely recognition of TPP2 deficiency is crucial since (1) immune surveillance is needed and hematopoietic stem cell transplantation may be necessary, and (2) for provision of genetic counseling. Additionally, enzyme replacement therapy, as already established for TPP1 deficiency, might be an option in the future. This article is protected by copyright. All rights reserved.

Correction to: Journal of Clinical Immunology (2021) 41:1633–1647

Adenosine deaminase 2 deficiency (DADA2) is a genetic auto- inflammatory disease that most often presents in childhood, but that can also have a late onset in adulthood. It is characterized by vasculitis, mainly of the skin and nervous system most often in the form of a stroke, associated to immunodeficiency and cytopenias. The diagnosis is made by measuring adenosine deaminase 2 (ADA2) enzymatic activity and confirming the presence of mutations in the ADA2 gene by genetic testing. The treatment of choice for the inflammatory phenotype is the early administration of anti-TNFa to avoid the risk of major neurological disabilities. In the case of severe hematological involvement, hematopoietic stem cell transplantation is the only curative treatment currently available.Le déficit en adénosine désaminase 2 (DADA2) est une maladie génétique auto-inflammatoire qui se manifeste le plus souvent à l’âge pédiatrique mais qui peut également débuter à l’âge adulte. Il se caractérise par une atteinte vasculitique responsable d’altérations cutanées et d’AVC associée à une immunodéficience et des cytopénies. Le diagnostic de DADA2 est posé par le dosage de l’activité de l’adénosine désaminase 2 (ADA2) et la confirmation par un test génétique d’une mutation dans le gène

The pharmacokinetics of low-dose busulfan (BU) were investigated as a nonmyeloablative conditioning regimen for autologous gene therapy (GT) in pediatric subjects with adenosine deaminase-deficient severe combined immunodeficiency disease (ADA SCID). In 3 successive clinical trials, which included either γ-retroviral (γ-RV) or lentiviral (LV) vectors, subjects were conditioned with BU using different dosing nomograms. The first cohort received BU doses based on body surface area (BSA), the second cohort received doses based on actual body weight (ABW), and in the third cohort, therapeutic drug monitoring (TDM) was used to target a specific area under the concentration-time curve (AUC). Neither BSA-based nor ABW-based dosing achieved a consistent cumulative BU AUC; in contrast, TDM-based dosing led to more consistent AUC. BU clearance increased as subject age increased from birth to 18 months. However, weight and age alone were insufficient to accurately predict the dose that would consistently achieve a target AUC. Furthermore, various clinical, laboratory, and genetic factors (eg, genotypes for glutathione-S-transferase isozymes known to participate in BU metabolism) were analyzed, but no single finding predicted subjects with rapid versus slow clearance. Analysis of BU AUC and the postengraftment vector copy number (VCN) in granulocytes, a surrogate marker of the level of engrafted gene-modified hematopoietic stem and progenitor cells (HSPCs), demonstrated gene marking at levels sufficient for therapeutic benefit in the subjects who had achieved the target BU AUC. Although many factors determine the ultimate engraftment following GT, this work demonstrates that the BU AUC correlated with the eventual level of engrafted gene-modified HSPCs within a vector group (γ-RV versus LV), with significantly higher levels of granulocyte VCN in the recipients of LV-modified grafts compared to recipients of γ-RV-transduced grafts. Taken together, these findings provide insight into low-dose BU pharmacokinetics in the unique setting of autologous GT for ADA SCID, and these dosing principles may be applied to future GT trials using low-dose BU to open the bone marrow niche.

Corria o ano de 1992 em Atlanta, quando um recém-famoso rapper foi convidado para discursar num banquete organizado pelo Malcolm X Grassroots Movement, que já era então um dos mais importantes movimentos negros existentes nos EUA. O rapper é apresentado por um ilustre membro desse movimento, Watani Tyehimba, como “uma pessoa muito querida para mim, uma pessoa que é um revolucionário da segunda geração”. Watani – que logo se tornaria seu braço direito – o conhecia desde criança. Havia lutado ao lado de sua família junto ao Black Panthers Party for Self Defense nos anos 1960 e 70. Havia, por isso, acompanhado seu crescimento. Sabia que sua mãe, Afeni Shakur, havia sido presa duas vezes e passado quase toda a gravidez na prisão, de onde saiu para ser perseguida pelo resto da vida, para ter suas menores lutas esmagadas, para não conseguir emprego em lugar algum e ser obrigada a migrar de tempos em tempos, para passar fome e se viciar em crack. Sabia que seu pai de sangue os havia abandonado e que seus tios e padrastos haviam sido todos presos ou mortos. Sabia ainda que, apesar de todas as desgraças, sua educação havia honrado seu nome (uma homenagem a dois chefes indígenas andinos), que havia sido criado como um verdadeiro black prince e que nos anos 1980 ocupara a posição de chairperson da organização juvenil New Afrikan Panthers. Acima de tudo, Watani sabia aquilo que todos ali sabiam: que aos 21 anos de idade, além de ter vendido algumas centenas de milhares de cópias do primeiro álbum, de ter lançado um videoclipe visto em todos os EUA que conta a história de Brenda, uma jovem mãe solteira 3 , esse rapper havia conquistado muito rapidamente um imenso respeito nas ruas dos guetos, principalmente em Los Angeles, cidade que naquele mesmo ano – e pela segunda vez em menos de trinta anos – fora o palco de mais uma revolta popular que mobilizou a Defesa Nacional e resultara em cerca de 25 mil presos 4 . Carregado por essa memória dupla, dos movimentos sociais e das ruas, Tupac Amaru Shakur, o rapper, não sabe bem onde se posicionar, não sabe bem quando dizer “nós” e “vocês” ou “nós” e “eles”. Parece, entretanto, saber com bastante certeza que aquilo que aquele público precisava ouvir naquele momento dizia respeito justamente a essa dificuldade.

Purpose Deficiency of adenosine deaminase 2 (DADA2) is an inherited inborn error of immunity, characterized by autoinflammation (recurrent fever), vasculopathy (livedo racemosa, polyarteritis nodosa, lacunar ischemic strokes, and intracranial hemorrhages), immunodeficiency, lymphoproliferation, immune cytopenias, and bone marrow failure (BMF). Tumor necrosis factor (TNF-α) blockade is the treatment of choice for the vasculopathy, but often fails to reverse refractory cytopenia. We aimed to study the outcome of hematopoietic cell transplantation (HCT) in patients with DADA2. Methods We conducted a retrospective study on the outcome of HCT in patients with DADA2. The primary outcome was overall survival (OS). Results Thirty DADA2 patients from 12 countries received a total of 38 HCTs. The indications for HCT were BMF, immune cytopenia, malignancy, or immunodeficiency. Median age at HCT was 9 years (range: 2–28 years). The conditioning regimens for the final transplants were myeloablative (n = 20), reduced intensity (n = 8), or non-myeloablative (n = 2). Donors were HLA-matched related (n = 4), HLA-matched unrelated (n = 16), HLA-haploidentical (n = 2), or HLA-mismatched unrelated (n = 8). After a median follow-up of 2 years (range: 0.5–16 years), 2-year OS was 97%, and 2-year GvHD-free relapse-free survival was 73%. The hematological and immunological phenotypes resolved, and there were no new vascular events. Plasma ADA2 enzyme activity normalized in 16/17 patients tested. Six patients required more than one HCT. Conclusion HCT was an effective treatment for DADA2, successfully reversing the refractory cytopenia, as well as the vasculopathy and immunodeficiency. Clinical Implications HCT is a definitive cure for DADA2 with > 95% survival.

Children appeared to be initially spared by the SARS-CoV-2 pandemic, however, in spring 2020, a new clinical entity was described related to the SARS-CoV-2 infection and named multisystem inflammatory syndrome in children (MIS-C) or pediatric inflammatory multisystem syndrome (PIMS). The gravity of this inflammatory syndrome, the time interval between infection and MIS-C, the response to the various immunomodulatory treatments are all suggestive of an immunologic reaction rather than a virus-mediatred phenomenon. The pathophysiological mechanisms and possible risk factors for MIS-C have not been elucidated. In this article, we summarize what is known to date about the immune response to SARS-CoV-2 in children and about the immune response to SARS-CoV-2 in children and about the MIS-C.Alors que les enfants semblaient épargnés par la pandémie due au SARS-CoV-2, une nouvelle entité clinique a été décrite au printemps 2020 en lien avec cette infection et appelée syndrome inflammatoire multisystémique de l’enfant (MIS-C ou PIMS en anglais). La gravité du syndrome inflammatoire, le délai entre l’infection et le MIS-C, et la réponse aux différents traitements immunomodulateurs sont tous suggestifs d’une réaction immunologique plutôt que d’un phénomène uniquement médié par le virus. Les mécanismes physiopathologiques et les facteurs de risque possibles du MIS-C n’ont pas encore été élucidés. Dans cet article, nous résumons ce qui est connu à ce jour sur la réponse immune au SARS-CoV-2 chez l’enfant et sur le MIS-C.

Severe Combined Immunodeficiency (SCID) is one of the most severe forms of Primary Immunodeficiencies (PID) and leads to a potentially fatal course of disease without early and definitive treatment. Adequate management, from the first days of life, can improve the survival and outcome of patients with SCID. This can be achieved through newborn screening (NBS) based on the measurement of T-cell receptor excision circles (TREC). Already present in many countries, this NBS test was introduced in Switzerland in January 2019 on a pilot phase. In addition to the assessment of TRECs, the measurement of kappa recombinant excision circles (KREC) has also been introduced at the same time and allows the identification of severe forms of PID characterized by profound B cell lymphopenia.Le déficit immunitaire combiné sévère (DICS) fait partie des formes sévères d’immunodéficience primaire (IDP) avec un tableau clinique fatal sans traitement précoce et définitif, comme la transplantation des cellules souches hématopoïétiques. Une prise en charge adéquate dès les premiers jours de vie va permettre d’améliorer le devenir des patients avec DICS. Une meilleure prise en charge est devenue possible grâce au dépistage néonatal basé sur la mesure des cercles d’excision des récepteurs des cellules T. Ce test a été introduit en Suisse dans une phase pilote à partir de janvier 2019, avec un dépistage supplémentaire via le dosage des cercles d’excision des recombinants Kappa, qui permet d’identifier des formes graves d’IDP se manifestant surtout par une lymphopénie B profonde.

Patients lacking functional adenosine deaminase activity have severe combined immunodeficiency (ADA SCID), which can be treated with ADA enzyme replacement therapy (ERT), allogeneic hematopoietic stem cell transplantation (HSCT), or autologous HSCT with gene-corrected cells (gene therapy [GT]). A cohort of 10 ADA SCID patients, aged 3 months to 15 years, underwent GT in a phase 2 clinical trial between 2009 and 2012. Autologous bone marrow CD34+ cells were transduced ex vivo with the MND (myeloproliferative sarcoma virus, negative control region deleted, dl587rev primer binding site)–ADA gammaretroviral vector (gRV) and infused following busulfan reduced-intensity conditioning. These patients were monitored in a long-term follow-up protocol over 8 to 11 years. Nine of 10 patients have sufficient immune reconstitution to protect against serious infections and have not needed to resume ERT or proceed to secondary allogeneic HSCT. ERT was restarted 6 months after GT in the oldest patient who had no evidence of benefit from GT. Four of 9 evaluable patients with the highest gene marking and B-cell numbers remain off immunoglobulin replacement therapy and responded to vaccines. There were broad ranges of responses in normalization of ADA enzyme activity and adenine metabolites in blood cells and levels of cellular and humoral immune reconstitution. Outcomes were generally better in younger patients and those receiving higher doses of gene-marked CD34+ cells. No patient experienced a leukoproliferative event after GT, despite persisting prominent clones with vector integrations adjacent to proto-oncogenes. These long-term findings demonstrate enduring efficacy of GT for ADA SCID but also highlight risks of genotoxicity with gRVs. This trial was registered at www.clinicaltrials.gov as #NCT00794508.

Clinical data from ADA-SCID patients registered in the U.S. Immunodeficiency Network (USIDNet) Repository were analyzed. Sixty-four ADA-SCID patients born between 1981 and 2017 had clinical data entered by their local (or home) enrolling institution. Median age at diagnosis was 1month for those with a positive family history and 3months for those without a prior family history, with some diagnosed at birth and one as late as 9years of age. Overall survival was 79.7%, which increased to 94.1% since 2010. These patients had multiple infections and pulmonary, gastrointestinal, and neurological complications. The majority received enzyme replacement therapy (ERT) at some time, including 88% of those born since 2010. Twenty-six patients underwent allogeneic hematopoietic stem cell transplant (HSCT). HSCT successfully supported survival (17/26, 65%) using a variety of cell sources (bone marrow, mobilized peripheral blood, and cord blood) from sibling, family and unrelated donors. Nineteen patients underwent autologous HSCT with gene therapy (GT) using retroviral and lentiviral vectors and all are surviving. The prognosis for patients with ADA-SCID has continued to improve but these patients do have multiple early and potentially long-term conditions that require medical monitoring and management.

Early malnutrition, the first environmental cause of intra-uterine growth restriction, impairs development of the thymus. Alterations of the thymic structure and function are reported at young ages in murine and ovine models. However, descriptions of thymic consequences of fetal malnutrition at adulthood are scarce. The present study investigates thymic structure, protein expression and cell selection process observed at postnatal day 180 (PND180) in male offspring of rats exposed to maternal low-protein diet (mLPD) compared with control diet during gestation. The thymic index was lower in adult offspring exposed to mLPD (P P β receptor (P P P P

Severe combined immune deficiency, also known by its acronym, SCID, was once inevitably fatal in infancy. In the 1970s, our understanding was limited to a description of thymic dysplasia and lymphopenia with no immunoglobulins. Although the first bone marrow transplant was done in 1958, there was little understanding of the variables impacting success and the next ten years saw advances in HLA typing and general understanding of the hematopoietic system, leading to the first transplant for SCID in 1968. Today, hematopoietic stem cell transplants are successful for SCID >90% of the time when the patient is identified through newborn screening. In parallel with treatment advances have been a wealth of diagnostic advances. This chapter will cover the individual types of SCID.

Mutations in the gene AK2 are responsible for reticular dysgenesis (RD), a rare and severe form of primary immunodeficiency in children. RD patients have a severely shortened life expectancy and without treatment die, generally from sepsis soon after birth. The only available therapeutic option for RD is hematopoietic stem cell transplantation (HSCT). To gain insight into the pathophysiology of RD, we previously created zebrafish models for Ak2 deficiencies. One of the clinical features of RD is hearing loss, but its pathophysiology and causes have not been determined. In adult mammals, sensory hair cells of the inner ear do not regenerate; however, their regeneration has been observed in several non-mammalian vertebrates, including zebrafish. Therefore, we used our RD zebrafish models to determine whether Ak2 deficiency affects sensory organ development and/or hair cell regeneration. Our studies indicated that Ak2 is required for the correct development, survival and regeneration of sensory hair cells. Interestingly, Ak2 deficiency induces the expression of several oxidative stress markers and it triggers an increased level of cell death in the hair cells. Finally, we show that glutathione treatment can partially rescue hair cell development in the sensory organs in our RD models, pointing to the potential use of antioxidants as a therapeutic treatment supplementing HSCT to prevent or ameliorate sensorineural hearing deficits in RD patients., Summary: A zebrafish model of reticular dysgenesis reveals hair cell developmental deficits that can be partially rescued by antioxidants, pointing to their potential use as a therapeutic treatment for reticular dysgenesis patients.

Introduction: Adenosine deaminase (ADA) deficiency was the first human disease treated with gene therapy. Initial trials established proofs of concepts, but did not lead to cure of the severe combined immune deficiency that is the hallmark of this disease. A breakthrough trial combined gammaretroviral gene therapy with non-myeloablative conditioning of subjects unable to benefit from enzyme replacement therapy (ERT) with pegylated bovine ADA (PEG-ADA). Three additional trials have confirmed the ability of gene therapy to cure the clinical immune defect of ADA deficiency.Areas covered: This article reviews the development of gene therapy for ADA-SCID, compares the four trials that have been reported and discusses open questions remaining in the field.Expert opinion: Gene therapy may be regarded as standard of care for the majority of patients with ADA deficiency, along with allogeneic hematopoietic cell transplantation (HCT) or ERT. The appropriate sequencing of these treatments remains uncertain. ...