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Alessandro Aiuti - One of the best experts on this subject based on the ideXlab platform.
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autoimmune dysregulation and purine metabolism in Adenosine Deaminase Deficiency
Frontiers in Immunology, 2012Co-Authors: Aisha V Sauer, Immacolata Brigida, Nicola Carriglio, Alessandro AiutiAbstract:Genetic defects in the Adenosine Deaminase (ADA) gene are among the most common causes for severe combined immunoDeficiency (SCID). ADA-SCID patients suffer from lymphopenia, severely impaired cellular and humoral immunity, failure to thrive and recurrent infections. Currently available therapeutic options for this otherwise fatal disorder include bone marrow transplantation (BMT), enzyme replacement therapy with bovine ADA (PEG-ADA) or hematopoietic stem cell gene therapy (HSC-GT). Although varying degrees of immune reconstitution can be achieved by these treatments, breakdown of tolerance is a major concern in ADA-SCID. Immune dysregulation such as autoimmune hypothyroidism, diabetes mellitus, hemolytic anemia, and immune thrombocytopenia are frequently observed in milder forms of the disease. However, several reports document similar complications also in patients on long-term PEG-ADA and after BMT or GT treatment. A skewed repertoire and decreased immune functions have been implicated in autoimmunity observed in certain B-cell and/or T-cell immunodeficiencies, but it remains unclear to what extent specific mechanisms of tolerance are affected in ADA Deficiency. Herein we provide an overview about ADA-SCID and the autoimmune manifestations reported in these patients before and after treatment. We also assess the value of the ADA-deficient mouse model as a useful tool to study both immune and metabolic disease mechanisms. With focus on regulatory T and B cells we discuss the lymphocyte subpopulations particularly prone to contribute to the loss of self-tolerance and onset of autoimmunity in ADA Deficiency. Moreover we address which aspects of immune dysregulation are specifically related to alterations in purine metabolism caused by the lack of ADA and the subsequent accumulation of metabolites with immunomodulatory properties.
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Gene Therapy for Adenosine Deaminase Deficiency
Immunology and allergy clinics of North America, 2010Co-Authors: Barbara Cappelli, Alessandro AiutiAbstract:In the last decade, gene therapy for Adenosine Deaminase Deficiency has been developed as a successful alternative strategy to allogeneic bone marrow transplant and enzyme replacement therapy. Infusion of autologous hematopoietic stem cells, corrected ex vivo by retroviral vectors and combined to low-intensity conditioning regimen, has resulted in immunologic improvement, metabolic correction, and long-term clinical benefits. These findings have opened the way to applications of gene therapy in other primary immune deficiencies using novel vector technology.
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gene therapy for immunoDeficiency due to Adenosine Deaminase Deficiency
The New England Journal of Medicine, 2009Co-Authors: Alessandro Aiuti, Federica Cattaneo, Stefania Galimberti, Ulrike Benninghoff, Barbara Cassani, Luciano Callegaro, Samantha Scaramuzza, Grazia Andolfi, Massimiliano Mirolo, Immacolata BrigidaAbstract:Background We investigated the long-term outcome of gene therapy for severe combined immunoDeficiency (SCID) due to the lack of Adenosine Deaminase (ADA), a fatal disorder of purine metabolism and immunoDeficiency. Methods We infused autologous CD34+ bone marrow cells transduced with a retroviral vector containing the ADA gene into 10 children with SCID due to ADA Deficiency who lacked an HLA-identical sibling donor, after nonmyeloablative conditioning with busulfan. Enzyme-replacement therapy was not given after infusion of the cells. Results All patients are alive after a median follow-up of 4.0 years (range, 1.8 to 8.0). Transduced hematopoietic stem cells have stably engrafted and differentiated into myeloid cells containing ADA (mean range at 1 year in bone marrow lineages, 3.5 to 8.9%) and lymphoid cells (mean range in peripheral blood, 52.4 to 88.0%). Eight patients do not require enzyme-replacement therapy, their blood cells continue to express ADA, and they have no signs of defective detoxificati...
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Capillary Electrophoresis in Diagnosis and Monitoring of Adenosine Deaminase Deficiency
Clinical chemistry, 2003Co-Authors: Filippo Carlucci, Alessandro Aiuti, Antonella Tabucchi, Francesca Rosi, F. Floccari, Roberto Pagani, Enrico MarinelloAbstract:Background: The diagnosis and monitoring of severe combined immunoDeficiency disease (SCID) attributable to Adenosine Deaminase (ADA) Deficiency requires measurements of ADA, purine nucleoside phosphorylase (PNP), and S -adenosyl-l-homocysteine-hydrolase (SAHH) activity and of deoxyAdenosine metabolites. We developed capillary electrophoresis (CE) methods for the detection of key diagnostic metabolites and evaluation of enzyme activities. Methods: DeoxyAdenosine metabolites were separated in 30 mmol/L sodium borate–10 mmol/L sodium dodecyl sulfate (pH 9.80) at 25 °C on a 60-cm uncoated capillary. For determination of enzyme activities, substrate–product separation and measurements were carried out in 20 mmol/L sodium borate (pH 10.00) at 25 °C on a 42-cm uncoated capillary. Results: Deoxynucleotides and deoxyAdenosine were readily detectable in erythrocytes and urine, respectively. Both methods were linear in the range 2–500 μmol/L ( r >0.99). Intra- and interassay CV were r >0.99 for both). In erythrocytes from healthy individuals, mean (SD) ADA activity was 5619 (2584) nmol/s per liter of packed cells. In erythrocytes of SCID patients at diagnosis, ADA activity was 56.9 (48.3) nmol/s per liter of packed cells; SAHH activity was also much reduced. PNP activity was similar in patients and controls. Conclusions: CE can be used to test ADA Deficiency and enables rapid assessment of ADA expression in hematopoietic cells of SCID patients during therapy.
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Gene therapy for Adenosine Deaminase Deficiency.
Current opinion in allergy and clinical immunology, 2003Co-Authors: Alessandro Aiuti, Francesca Ficara, Federica Cattaneo, Claudio Bordignon, Maria Grazia RoncaroloAbstract:Purpose of review Gene therapy for severe combined immunoDeficiency due to Adenosine Deaminase Deficiency has moved from the early trials of safety and feasibility to recent studies demonstrating efficacy and clinical benefit. This review describes the latest advances in gene therapy trials for this condition using peripheral blood lymphocytes or hematopoietic progenitors. Recent findings In the first patients with severe combined immunoDeficiency due to Adenosine Deaminase Deficiency treated with peripheral blood lymphocytes, transduced T cells have been shown to persist for over 10 years, expressing transgenic Adenosine Deaminase, but the therapeutic effect of gene therapy remained difficult to assess because of the concomitant treatment with bovine Adenosine Deaminase conjugated to polyethylene-glycol (PEG-ADA). A recent report showed that discontinuation of PEG-ADA resulted in a strong selective advantage of gene corrected T cells associated with restoration of T cell functions and antibody responses to neoantigen, but incomplete correction of the metabolic defect. Follow-up studies in patients treated with engineered hematopoietic progenitors in the early trials revealed low marking levels of long-term living progenitors and limited clinical effect. Recently, an improved gene transfer protocol in bone marrow CD34+ cells combined with low-dose busulfan resulted in multilineage, stable engraftment of transduced progenitors at substantial levels, restoration of immune functions, correction of the Adenosine Deaminase metabolic defect, and proven clinical benefit, in the absence of PEG-ADA. Overall, no adverse effect or toxicity has been observed in patients treated with Adenosine Deaminase gene transfer in mature lymphocytes or hematopoietic progenitors. Summary Gene transfer in hematopoietic stem cells combined with nonmyeloablative conditioning is efficacious and might be extended to the treatment of other inherited and acquired disorders of the hematopoietic system.
Michael S. Hershfield - One of the best experts on this subject based on the ideXlab platform.
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Adenosine Deaminase Deficiency
2014Co-Authors: Michael S. HershfieldAbstract:Clinical characteristics Adenosine Deaminase (ADA) Deficiency is a systemic purine metabolic disorder that primarily affects lymphocyte development, viability, and function. The clinical phenotypic spectrum includes: Infants with typical early-onset ADA-deficient SCID have failure to thrive and opportunistic infections associated with marked depletion of T, B, and NK lymphocytes, and an absence of both humoral and cellular immune function. If immune function is not restored, children with ADA-deficient SCID rarely survive beyond age one to two years. Infections in delayed- and late-onset types (commonly, recurrent otitis, sinusitis, and upper respiratory) may initially be less severe than those in individuals with ADA-deficient SCID; however, by the time of diagnosis these individuals often have chronic pulmonary insufficiency and may have autoimmune phenomena (cytopenias, anti-thyroid antibodies), allergies, and elevated serum concentration of IgE. The longer the disorder goes unrecognized, the more immune function deteriorates and the more likely are chronic sequelae of recurrent infection. Diagnosis/testing The diagnosis of ADA Deficiency is established in a proband: Management Treatment of manifestations: Infections are treated with specific antibiotic, antifungal, and antiviral agents and administration of intravenous immunoglobulin (IVIg); prophylaxis is provided for Pneumocystis jiroveci infection. Prevention of primary manifestations: Restoration of a functional immune system is essential. The preferred treatment is bone marrow/stem cell transplantation (BMT/SCT) from an HLA-identical healthy sib or close relative. However, most individuals with ADA-deficient SCID lack an HLA-identical related donor. For these individuals, alternative therapies can be considered: Surveillance: Annual or more frequent evaluation of lymphocyte counts, serum immunoglobulin levels, and various in vitro tests of cellular and humoral immune function following BMT/SCT and during ERT (more frequent monitoring and other specialized testing would be required for participants in gene therapy trials). Individuals on ERT also require periodic monitoring of PEG-ADA levels in plasma and metabolite levels in erythrocytes, and under some circumstances testing for anti-ADA antibodies. Agents/circumstances to avoid: The use of adenine arabinoside (a substrate for ADA) as an antiviral agent or for chemotherapy of malignancies should be avoided; pentostatin, a potent ADA inhibitor used to treat some lymphoid malignancies, would be ineffective in persons who lack ADA, and would interfere with PEG-ADA. Evaluation of relatives at risk: In the newborn sibs of a proband, it is appropriate to either assay ADA catalytic activity or perform molecular genetic testing (if the family-specific pathogenic variants are known), so that morbidity and mortality can be reduced by early diagnosis and treatment. Genetic counseling ADA Deficiency is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk family members and prenatal testing for pregnancies at increased risk are possible once the pathogenic variants have been identified in the family.
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successful bone marrow transplantation with reduced intensity conditioning in a patient with delayed onset Adenosine Deaminase Deficiency
Pediatric Transplantation, 2013Co-Authors: Hirokazu Kanegane, Michael S. Hershfield, Ines Santisteban, Hiromichi Taneichi, Keiko Nomura, Taizo Wada, Akihiro Yachie, Kohsuke Imai, Tadashi Ariga, Toshio MiyawakiAbstract:Kanegane H, Taneichi H, Nomura K, Wada T, Yachie A, Imai K, Ariga T, Santisteban I, Hershfield MS, Miyawaki T. Successful bone marrow transplantation with reduced intensity conditioning in a patient with delayed-onset Adenosine Deaminase Deficiency. Abstract: In this case report, we describe successful BMT with RIC in a patient with delayed-onset ADA Deficiency. A three-yr-old Japanese boy was diagnosed with delayed-onset ADA Deficiency because of recurrent bronchitis, bronchiectasia, and lymphopenia. In addition, autoimmune thyroiditis and neutropenia were present. At four yr of age, he underwent BMT with a RIC regimen, including busulfan and fludarabine, from an HLA-identical healthy sister. Engraftment after BMT was uneventful without GVHD. Decreased ADA levels in blood immediately increased following BMT, and the patient was disease-free 13 months after BMT. These results suggest that BMT with RIC may sufficiently restore immune regulation in delayed-onset ADA Deficiency. A longer follow-up period is needed to confirm these observations.
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Successful bone marrow transplantation with reduced intensity conditioning in a patient with delayed‐onset Adenosine Deaminase Deficiency
Pediatric transplantation, 2012Co-Authors: Hirokazu Kanegane, Michael S. Hershfield, Ines Santisteban, Hiromichi Taneichi, Keiko Nomura, Taizo Wada, Akihiro Yachie, Kohsuke Imai, Tadashi Ariga, Toshio MiyawakiAbstract:Kanegane H, Taneichi H, Nomura K, Wada T, Yachie A, Imai K, Ariga T, Santisteban I, Hershfield MS, Miyawaki T. Successful bone marrow transplantation with reduced intensity conditioning in a patient with delayed-onset Adenosine Deaminase Deficiency. Abstract: In this case report, we describe successful BMT with RIC in a patient with delayed-onset ADA Deficiency. A three-yr-old Japanese boy was diagnosed with delayed-onset ADA Deficiency because of recurrent bronchitis, bronchiectasia, and lymphopenia. In addition, autoimmune thyroiditis and neutropenia were present. At four yr of age, he underwent BMT with a RIC regimen, including busulfan and fludarabine, from an HLA-identical healthy sister. Engraftment after BMT was uneventful without GVHD. Decreased ADA levels in blood immediately increased following BMT, and the patient was disease-free 13 months after BMT. These results suggest that BMT with RIC may sufficiently restore immune regulation in delayed-onset ADA Deficiency. A longer follow-up period is needed to confirm these observations.
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IMMUNODeficiency CAUSED BY Adenosine Deaminase Deficiency
Immunology and Allergy Clinics of North America, 2000Co-Authors: Michael S. HershfieldAbstract:Deficiency of Adenosine Deaminase (ADA), an enzyme of purine nucleoside metabolism, is found in about 15% of all patients with severe combined immunoDeficiency disease (SCID), or in 30% to 40% of those with autosomal recessive inheritance. 12,41,75 ADA Deficiency is also associated with milder degrees of immune Deficiency that are compatible with survival beyond early childhood. The enzyme Deficiency should be considered in the differential diagnosis of children and adults with a history of serious and recurrent infections who have persistent lymphopenia and findings indicating both cellular and humoral immune dysfunction. Determining whether a patient with SCID is ADA-deficient is important for genetic counseling, but also for reasons related to the systemic metabolic disorder. Even though devastating consequences of immunoDeficiency dominate the clinical presentation, ADA Deficiency may cause nonlymphoid pathology over time. There are presently more treatment options available for ADA Deficiency than for SCID caused by other genetic defects. These options include bone marrow transplantation (BMT), enzyme replacement, and gene therapy. This article summarizes the clinical presentation and diagnosis of ADA Deficiency, metabolic and genetic factors that underlie immunoDeficiency and influence disease severity, and provides an overview of the status of current therapies. A more comprehensive review can be found in Hershfield and Mitchell (an updated version is in press). 41
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Adenosine Deaminase Deficiency clinical expression molecular basis and therapy
Seminars in Hematology, 1998Co-Authors: Michael S. HershfieldAbstract:Adenosine Deaminase (ADA) Deficiency is the first known cause of severe combined immunoDeficiency disease (SCID). Over the past 25 years, the metabolic basis for immune Deficiency has largely been established. The clinical spectrum associated with ADA Deficiency is now quite broad, including older children and adults. The ADA gene has been sequenced, the structure of the enzyme has been determined, and over 50 ADA gene mutations have been identified. There appears to be a quantitative relationship between residual ADA activity, determined by genotype, and both metabolic and clinical phenotype. ADA Deficiency has become a focus for novel approaches to enzyme replacement and gene therapy. Enzyme replacement with polyethylene glycol (PEG)-modified ADA, used to treat patients who lack a human leukocyte antigen (HLA)-matched bone marrow donor, is safe and effective, but expensive. Several approaches to gene therapy have been investigated in patients receiving PEG-ADA. Persistent expression of transduced ADA cDNA in T lymphocytes and myeloid cells has occurred in a few patients, but significant improvement in immune function because of the transduced cells has not been shown. The major barrier to effective gene therapy remains the low efficiency of stem cell transduction with retroviral vectors.
Immacolata Brigida - One of the best experts on this subject based on the ideXlab platform.
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autoimmune dysregulation and purine metabolism in Adenosine Deaminase Deficiency
Frontiers in Immunology, 2012Co-Authors: Aisha V Sauer, Immacolata Brigida, Nicola Carriglio, Alessandro AiutiAbstract:Genetic defects in the Adenosine Deaminase (ADA) gene are among the most common causes for severe combined immunoDeficiency (SCID). ADA-SCID patients suffer from lymphopenia, severely impaired cellular and humoral immunity, failure to thrive and recurrent infections. Currently available therapeutic options for this otherwise fatal disorder include bone marrow transplantation (BMT), enzyme replacement therapy with bovine ADA (PEG-ADA) or hematopoietic stem cell gene therapy (HSC-GT). Although varying degrees of immune reconstitution can be achieved by these treatments, breakdown of tolerance is a major concern in ADA-SCID. Immune dysregulation such as autoimmune hypothyroidism, diabetes mellitus, hemolytic anemia, and immune thrombocytopenia are frequently observed in milder forms of the disease. However, several reports document similar complications also in patients on long-term PEG-ADA and after BMT or GT treatment. A skewed repertoire and decreased immune functions have been implicated in autoimmunity observed in certain B-cell and/or T-cell immunodeficiencies, but it remains unclear to what extent specific mechanisms of tolerance are affected in ADA Deficiency. Herein we provide an overview about ADA-SCID and the autoimmune manifestations reported in these patients before and after treatment. We also assess the value of the ADA-deficient mouse model as a useful tool to study both immune and metabolic disease mechanisms. With focus on regulatory T and B cells we discuss the lymphocyte subpopulations particularly prone to contribute to the loss of self-tolerance and onset of autoimmunity in ADA Deficiency. Moreover we address which aspects of immune dysregulation are specifically related to alterations in purine metabolism caused by the lack of ADA and the subsequent accumulation of metabolites with immunomodulatory properties.
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gene therapy for immunoDeficiency due to Adenosine Deaminase Deficiency
The New England Journal of Medicine, 2009Co-Authors: Alessandro Aiuti, Federica Cattaneo, Stefania Galimberti, Ulrike Benninghoff, Barbara Cassani, Luciano Callegaro, Samantha Scaramuzza, Grazia Andolfi, Massimiliano Mirolo, Immacolata BrigidaAbstract:Background We investigated the long-term outcome of gene therapy for severe combined immunoDeficiency (SCID) due to the lack of Adenosine Deaminase (ADA), a fatal disorder of purine metabolism and immunoDeficiency. Methods We infused autologous CD34+ bone marrow cells transduced with a retroviral vector containing the ADA gene into 10 children with SCID due to ADA Deficiency who lacked an HLA-identical sibling donor, after nonmyeloablative conditioning with busulfan. Enzyme-replacement therapy was not given after infusion of the cells. Results All patients are alive after a median follow-up of 4.0 years (range, 1.8 to 8.0). Transduced hematopoietic stem cells have stably engrafted and differentiated into myeloid cells containing ADA (mean range at 1 year in bone marrow lineages, 3.5 to 8.9%) and lymphoid cells (mean range in peripheral blood, 52.4 to 88.0%). Eight patients do not require enzyme-replacement therapy, their blood cells continue to express ADA, and they have no signs of defective detoxificati...
Floyd F. Snyder - One of the best experts on this subject based on the ideXlab platform.
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Genetic Models of Purine Nucleoside Phosphorylase Deficiency in the Mouse
Advances in experimental medicine and biology, 1991Co-Authors: Floyd F. SnyderAbstract:Purine nucleoside phosphorylase Deficiency is associated with severe T cell immunoDeficiency disease1 and more recently behavioral and neurological features have also been described2,3. With respect to presentation, this disease appears intermediary in phenotype to the severe combined immunoDeficiency disease of Adenosine Deaminase Deficiency and the severe neurological impairment associated with complete HPRT Deficiency.
Hubert B. Gaspar - One of the best experts on this subject based on the ideXlab platform.
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Adenosine Deaminase Deficiency – More Than Just an ImmunoDeficiency
Frontiers in immunology, 2016Co-Authors: Kathryn Victoria Whitmore, Hubert B. GasparAbstract:Adenosine Deaminase (ADA) Deficiency is best known as a form of severe combined immunoDeficiency (SCID) that results from mutations in the gene encoding ADA. Affected patients present with clinical and immunological manifestations typical of a SCID. Therapies are currently available that can target these immunological disturbances and treated patients show varying degrees of clinical improvement. However, there is now a growing body of evidence that Deficiency of ADA has significant impact on non-immunological organ systems. This review will outline the impact of ADA Deficiency on various organ systems, starting with the well-understood immunological abnormalities. We will discuss possible pathogenic mechanisms and also highlight ways in which current treatments could be improved. In doing so, we aim to present ADA Deficiency as more than an immunoDeficiency and suggest that it should be recognized as a systemic metabolic disorder that affects multiple organ systems. Only by fully understanding ADA Deficiency and its manifestations in all organ systems can we aim to deliver therapies that will correct all the clinical consequences.
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Bilateral sensorineural deafness in Adenosine Deaminase-deficient severe combined immunoDeficiency.
The Journal of pediatrics, 2004Co-Authors: Wendy Albuquerque, Hubert B. GasparAbstract:Adenosine Deaminase Deficiency presents with severe combined immunoDeficiency and is treatable by bone marrow transplantation. With improved survival, the nonimmunologic manifestations of this condition are becoming apparent. We report a high incidence of bilateral sensorineural deafness in transplanted patients, which highlights the systemic nature of the disease.