RARE DISEASE
Severe combined immunodeficiency due to adenosine deaminase deficiency
Severe combined immunodeficiency due to adenosine deaminase deficiency
Severe combined immunodeficiency due to adenosine deaminase deficiency
Synonyms: ADA deficiency, SCID due to adenosine deaminase deficiency
Synonyms: ADA deficiency, SCID due to adenosine deaminase deficiency
Synonyms: ADA deficiency, SCID due to adenosine deaminase deficiency
Drug discovery
6
drugs
With orphan designations
Overview
Severe combined immunodeficiency due to adenosine deaminase deficiency (ADA-SCID) is an autosomal recessive disorder caused by ADA gene mutations (20q13.11), leading to toxic purine metabolite accumulation, profound lymphopenia (T-, B-, NK-cell deficiency), and life-threatening infections. Patients may present with systemic manifestations, including neurodevelopmental deficits, skeletal abnormalities, and pulmonary alveolar proteinosis. Diagnosis involves low ADA activity, elevated dATP, and genetic testing. Untreated cases are typically fatal by age 2 [1][2][9].
Burden
Untreated: Mortality approaches 100% by age 2 due to opportunistic infections [4][19].
Survivors face risks of neurodevelopmental delays, chronic pulmonary disease, and malignancy [9][15].
High healthcare costs from ERT, HSCT complications, and long-term multidisciplinary care [9][16].
Early diagnosis via newborn screening improves outcomes significantly [14].
Therapies
Enzyme replacement therapy (ERT): Stabilizes patients with PEG-ADA but requires lifelong administration and offers incomplete immunity [8][17].
Hematopoietic stem cell transplantation (HSCT): Curative, with 72–86% 5-year survival for matched sibling donors but lower success with mismatched donors [2][16].
Gene therapy: Autologous CD34+ cell transplantation with ADA-corrected vectors achieves >90% 5-year survival and sustained immune reconstitution [3][12][16].
Categories: rare genetic diseases, rare immunological diseases, rare inborn errors of metabolism, rare transplant-related disorders
Research Papers
484 drug discovery papers about Severe combined immunodeficiency due to adenosine deaminase deficiency, with 2 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
484 drug discovery papers about Severe combined immunodeficiency due to adenosine deaminase deficiency, with 2 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2025-12-04 | Chlamydomonas Cellular Phenotypes Enable in vivo Validation of Computationally Designed Therapeutic ADA1 Variants
Poster presented at CellBio 2025 in Philadelphia, PA. December 2025Abstract:Adenosine deaminase (ADA) deficiency causes severe combined immunodeficiency, and current treatments include enzyme replacement therapy with immunogenic bovine proteins. To develop improved therapeutic variants, robust model systems are needed for testing rationally designed enzymes in vivo. We used Zoogle (zoogle.arcadiascience.com), a computational dataset that selects model organisms based on conserved protein characteristics rather than sequence similarity, to identify Chlamydomonas reinhardtii as an optimal system for studying human ADA1 function. This approach can identify effective models that traditional phylogenetic methods might overlook. We characterized Chlamydomonas ADA1 mutants and found clear phenotypic defects in motility and cellular metabolism, particularly altered starch accumulation under nutrient stress. We established quantitative phenotyping approaches, including high-throughput motility tracking, metabolic profiling via Raman spectroscopy, and biochemical staining to assess cellular function. These multi-modal readouts provided robust, reproducible measures of ADA1 activity in living cells. We're validating this system using wild-type human ADA1 and candidate variants designed through machine learning approaches to enhance stability and improve therapeutic properties. Initial results demonstrate that the algal system can detect functional differences in ADA1 variants, establishing a platform for screening computationally designed proteins. This approach enables systematic evaluation of engineered enzymes in a physiologically relevant cellular context. Our work establishes Chlamydomonas as an effective model for human metabolic enzymes and demonstrates the power of protein characteristic-based organism selection over traditional phylogenetic approaches. This validation platform enables rapid, cost-effective screening of designed therapeutic proteins before advancing to mammalian studies, potentially accelerating the development of next-generation enzyme replacement therapies for genetic diseases.
2025-11-25 | Outcomes following matched sibling donor transplantation for severe combined immunodeficiency: a report from the PIDTC
ABSTRACT: The Primary Immune Deficiency Treatment Consortium performed a retrospective analysis of 133 patients with severe combined immunodeficiency (SCID) receiving matched sibling donor (MSD) hematopoietic cell transplantation (HCT) between 1980 and 2023 at 30 North American institutions. In this largest cohort of MSD outcomes in patients with SCID to date, we examined the impact of conditioning regimen and graft-versus-host disease (GVHD) prophylaxis on survival and immune recovery. Outcomes after MSD HCT for SCID were excellent. Patients without an active infection or failure to thrive (FTT) at the time of HCT had 5-year overall survival superior to those with infection or FTT. Acute and chronic GVHD outcomes were independent of GVHD prophylaxis, conditioning regimen, SCID type, or presence of maternal engraftment. Patients without active infection at the time of HCT had superior chronic GVHD-free event-free survival vs those with infection. T-cell reconstitution at 6 months was less likely achieved with use of GVHD prophylaxis or serotherapy, and in patients with leaky SCID or Omenn syndrome. At 6 months, 1 year, and 2-5 years, T-cell reconstitution was less likely with ADA, DCLRE1C, or RAG genotype. B-cell reconstitution at 1 year and 2-5 years was negatively affected by development of grade 2 to 4 or 3 to 4 acute GVHD. Conditioning did not affect T- or B-cell reconstitution. Our data suggest omitting conditioning and GVHD prophylaxis for patients with typical SCID did not negatively affect 5-year outcomes after MSD HCT, but the data are insufficient to recommend this approach for best long-term outcomes. This trial was registered at www.clinicaltrials.gov as #NCT01186913 and #NCT01346150.
2025-11-21 | Dupilumab for atopic manifestations in pediatric patients with inborn errors of immunity: efficacy and safety in a genetically diverse cohort
Background Inborn Errors of Immunity (IEI) are monogenic disorders that predispose patients to infections, autoimmunity, atopy, and malignancies. Severe Th2-driven atopic dermatitis and asthma are common in several IEIs, including DOCK8 deficiency, STAT3 loss-of-function, and Wiskott–Aldrich syndrome, often refractory to conventional therapies. Dupilumab, a monoclonal antibody targeting IL-4Rα, has shown promise in managing recalcitrant atopic dermatitis and asthma, but data in immunocompromised pediatric populations remain limited. Methods We conducted a single-center, retrospective observational cohort study with prospective follow-up of ten pediatric patients with genetically confirmed IEI and atopic manifestations. Patients received subcutaneous dupilumab (300 mg every 4 weeks for atopic dermatitis; every 2 weeks for severe asthma). Outcomes were assessed using the Eczema Area and Severity Index (EASI), Dermatology Life Quality Index (DLQI), Childhood Asthma Control Test (C-ACT), eosinophil counts, and infection frequency across four time points (baseline, 6 months, 12 months, >18 months). Results The cohort included ten patients (6 males, 4 females) with mutations in DOCK8 (n=5), CARD11 (n=2), STAT3 LOF (n=1), ADA (n=1), and PEPD (n=1). Of ten patients, nine received dupilumab for atopic dermatitis. Baseline EASI and DLQI scores were 34.33 and 25.0, respectively. Following dupilumab therapy, mean EASI decreased to 2.67 (p<0.001) and DLQI improved to 2.67 (p<0.001), with sustained response observed over 18 months. Peripheral eosinophil counts declined from 2.0×10 9 /L to 0.45×10 9 /L (p<0.001). One patient with severe asthma achieved C-ACT improvement from 10 to 26 with no subsequent exacerbations. Treatment was well-tolerated, with only mild conjunctivitis or transient hypereosinophilia reported. Notably, skin infections resolved, and no systemic or opportunistic infections were observed. Conclusion Dupilumab is a safe and highly effective therapeutic option for pediatric patients with IEI-associated atopic manifestations, improving clinical outcomes, quality of life, and infection profile while preserving immune function. These findings support broader application of dupilumab in patients with IEI and warrant further investigation in larger, multicenter studies.
2025-07-01 | Synthetic approaches and biological functions of 2 deoxyadenosine: A review of nucleoside chemistry and cellular dynamics
2′ Deoxyadenosine (dAdo) resides at the critical junction of de novo and salvage deoxyribonucleotide synthesis while salvage phosphorylation of dAdo replenishes the dATP-pool, the de novo pathway via ribonucleotide reductase (RNR) generates dNTPs from ribonucleotides. Disruption of this balance as typified in adenosine deaminase (ADA) deficiency causes intracellular dAdo and dATP accumulation, potent RNR inhibition, dNTP‐pool disruption and replication stress. Concurrently, synthetic modification of the dAdo scaffold has driven the development of analogues that exploit nucleoside transporters, resist deaminative inactivation and selectively accumulate in target cells to modulate DNA repair, immune signalling and mitochondrial DNA maintenance. This review presents a unified account of dAdo’s structural and molecular properties, its role in dNTP homeostasis and cellular dynamics, the pathological consequences of salvage/de novo dysregulation, and the latest synthetic and medicinal chemistry strategies built on the dAdo framework.
2025-06-27 | Adenosine and Adenosine Deaminase Contrary Manifestations in Immunity.
Adenosine (Ado) is an important purine that regulates numerous physiological functions. Adenosine deaminase (ADA) catalyses the irreversible deamination of Ado and its derivatives. Ado and ADA are the essential players in the immune system, but their roles often are opposite, mutually exclusive and competitive. This work presents several critical immune system situations demonstrating the conflicts between the functions of Ado and ADA. Ado suppresses immunity and inflammation by inhibiting lymphocyte proliferation. ADA supports the development of the immune system by metabolising Ado. In infectious and inflamed diseases, the increased ADA levels in tissue exudates decrease Ado concentration, aggravating inflammation. ADA inhibition is required to protect Ado and mitigate inflammation. In hereditary ADA deficiency, cytotoxic metabolites of Ado accumulate in lymphocytes and suppress immunity. ADA deficiency became the second cause of severe combined immunodeficiency (SCID). Enzyme replacement therapy using PEGylated ADA and ADA gene therapy are recognised in ADA-SCID treatment. The human immunodeficiency virus (HIV) hyperactivates host immune cells, resulting in super-inflammation and acquired immunodeficiency syndrome (AIDS). Cytotoxic derivatives of Ado suppress HIV-1 growth, whereas ADA inactivates cytotoxic nucleosides. ADA inhibition is required to prolong the elimination time and reduce the effective doses of anti-AIDS drugs. Ado levels elevate in the tumour microenvironment, promote immunity suppression and condition tumour cell evasion of immune surveillance. ADA neutralises Ado and restores immunity. Furthermore, ADA can simultaneously bind to the CD26 protein on lymphocytes and the A2AR receptors on antigen-presenting dendritic cells. Created CD26-ADA-A2AR complex bridges T and dendritic cells, stimulating T lymphocyte function.
2025-12-04 | Chlamydomonas Cellular Phenotypes Enable in vivo Validation of Computationally Designed Therapeutic ADA1 Variants
Poster presented at CellBio 2025 in Philadelphia, PA. December 2025Abstract:Adenosine deaminase (ADA) deficiency causes severe combined immunodeficiency, and current treatments include enzyme replacement therapy with immunogenic bovine proteins. To develop improved therapeutic variants, robust model systems are needed for testing rationally designed enzymes in vivo. We used Zoogle (zoogle.arcadiascience.com), a computational dataset that selects model organisms based on conserved protein characteristics rather than sequence similarity, to identify Chlamydomonas reinhardtii as an optimal system for studying human ADA1 function. This approach can identify effective models that traditional phylogenetic methods might overlook. We characterized Chlamydomonas ADA1 mutants and found clear phenotypic defects in motility and cellular metabolism, particularly altered starch accumulation under nutrient stress. We established quantitative phenotyping approaches, including high-throughput motility tracking, metabolic profiling via Raman spectroscopy, and biochemical staining to assess cellular function. These multi-modal readouts provided robust, reproducible measures of ADA1 activity in living cells. We're validating this system using wild-type human ADA1 and candidate variants designed through machine learning approaches to enhance stability and improve therapeutic properties. Initial results demonstrate that the algal system can detect functional differences in ADA1 variants, establishing a platform for screening computationally designed proteins. This approach enables systematic evaluation of engineered enzymes in a physiologically relevant cellular context. Our work establishes Chlamydomonas as an effective model for human metabolic enzymes and demonstrates the power of protein characteristic-based organism selection over traditional phylogenetic approaches. This validation platform enables rapid, cost-effective screening of designed therapeutic proteins before advancing to mammalian studies, potentially accelerating the development of next-generation enzyme replacement therapies for genetic diseases.
2025-11-25 | Outcomes following matched sibling donor transplantation for severe combined immunodeficiency: a report from the PIDTC
ABSTRACT: The Primary Immune Deficiency Treatment Consortium performed a retrospective analysis of 133 patients with severe combined immunodeficiency (SCID) receiving matched sibling donor (MSD) hematopoietic cell transplantation (HCT) between 1980 and 2023 at 30 North American institutions. In this largest cohort of MSD outcomes in patients with SCID to date, we examined the impact of conditioning regimen and graft-versus-host disease (GVHD) prophylaxis on survival and immune recovery. Outcomes after MSD HCT for SCID were excellent. Patients without an active infection or failure to thrive (FTT) at the time of HCT had 5-year overall survival superior to those with infection or FTT. Acute and chronic GVHD outcomes were independent of GVHD prophylaxis, conditioning regimen, SCID type, or presence of maternal engraftment. Patients without active infection at the time of HCT had superior chronic GVHD-free event-free survival vs those with infection. T-cell reconstitution at 6 months was less likely achieved with use of GVHD prophylaxis or serotherapy, and in patients with leaky SCID or Omenn syndrome. At 6 months, 1 year, and 2-5 years, T-cell reconstitution was less likely with ADA, DCLRE1C, or RAG genotype. B-cell reconstitution at 1 year and 2-5 years was negatively affected by development of grade 2 to 4 or 3 to 4 acute GVHD. Conditioning did not affect T- or B-cell reconstitution. Our data suggest omitting conditioning and GVHD prophylaxis for patients with typical SCID did not negatively affect 5-year outcomes after MSD HCT, but the data are insufficient to recommend this approach for best long-term outcomes. This trial was registered at www.clinicaltrials.gov as #NCT01186913 and #NCT01346150.
2025-11-21 | Dupilumab for atopic manifestations in pediatric patients with inborn errors of immunity: efficacy and safety in a genetically diverse cohort
Background Inborn Errors of Immunity (IEI) are monogenic disorders that predispose patients to infections, autoimmunity, atopy, and malignancies. Severe Th2-driven atopic dermatitis and asthma are common in several IEIs, including DOCK8 deficiency, STAT3 loss-of-function, and Wiskott–Aldrich syndrome, often refractory to conventional therapies. Dupilumab, a monoclonal antibody targeting IL-4Rα, has shown promise in managing recalcitrant atopic dermatitis and asthma, but data in immunocompromised pediatric populations remain limited. Methods We conducted a single-center, retrospective observational cohort study with prospective follow-up of ten pediatric patients with genetically confirmed IEI and atopic manifestations. Patients received subcutaneous dupilumab (300 mg every 4 weeks for atopic dermatitis; every 2 weeks for severe asthma). Outcomes were assessed using the Eczema Area and Severity Index (EASI), Dermatology Life Quality Index (DLQI), Childhood Asthma Control Test (C-ACT), eosinophil counts, and infection frequency across four time points (baseline, 6 months, 12 months, >18 months). Results The cohort included ten patients (6 males, 4 females) with mutations in DOCK8 (n=5), CARD11 (n=2), STAT3 LOF (n=1), ADA (n=1), and PEPD (n=1). Of ten patients, nine received dupilumab for atopic dermatitis. Baseline EASI and DLQI scores were 34.33 and 25.0, respectively. Following dupilumab therapy, mean EASI decreased to 2.67 (p<0.001) and DLQI improved to 2.67 (p<0.001), with sustained response observed over 18 months. Peripheral eosinophil counts declined from 2.0×10 9 /L to 0.45×10 9 /L (p<0.001). One patient with severe asthma achieved C-ACT improvement from 10 to 26 with no subsequent exacerbations. Treatment was well-tolerated, with only mild conjunctivitis or transient hypereosinophilia reported. Notably, skin infections resolved, and no systemic or opportunistic infections were observed. Conclusion Dupilumab is a safe and highly effective therapeutic option for pediatric patients with IEI-associated atopic manifestations, improving clinical outcomes, quality of life, and infection profile while preserving immune function. These findings support broader application of dupilumab in patients with IEI and warrant further investigation in larger, multicenter studies.
2025-07-01 | Synthetic approaches and biological functions of 2 deoxyadenosine: A review of nucleoside chemistry and cellular dynamics
2′ Deoxyadenosine (dAdo) resides at the critical junction of de novo and salvage deoxyribonucleotide synthesis while salvage phosphorylation of dAdo replenishes the dATP-pool, the de novo pathway via ribonucleotide reductase (RNR) generates dNTPs from ribonucleotides. Disruption of this balance as typified in adenosine deaminase (ADA) deficiency causes intracellular dAdo and dATP accumulation, potent RNR inhibition, dNTP‐pool disruption and replication stress. Concurrently, synthetic modification of the dAdo scaffold has driven the development of analogues that exploit nucleoside transporters, resist deaminative inactivation and selectively accumulate in target cells to modulate DNA repair, immune signalling and mitochondrial DNA maintenance. This review presents a unified account of dAdo’s structural and molecular properties, its role in dNTP homeostasis and cellular dynamics, the pathological consequences of salvage/de novo dysregulation, and the latest synthetic and medicinal chemistry strategies built on the dAdo framework.
2025-06-27 | Adenosine and Adenosine Deaminase Contrary Manifestations in Immunity.
Adenosine (Ado) is an important purine that regulates numerous physiological functions. Adenosine deaminase (ADA) catalyses the irreversible deamination of Ado and its derivatives. Ado and ADA are the essential players in the immune system, but their roles often are opposite, mutually exclusive and competitive. This work presents several critical immune system situations demonstrating the conflicts between the functions of Ado and ADA. Ado suppresses immunity and inflammation by inhibiting lymphocyte proliferation. ADA supports the development of the immune system by metabolising Ado. In infectious and inflamed diseases, the increased ADA levels in tissue exudates decrease Ado concentration, aggravating inflammation. ADA inhibition is required to protect Ado and mitigate inflammation. In hereditary ADA deficiency, cytotoxic metabolites of Ado accumulate in lymphocytes and suppress immunity. ADA deficiency became the second cause of severe combined immunodeficiency (SCID). Enzyme replacement therapy using PEGylated ADA and ADA gene therapy are recognised in ADA-SCID treatment. The human immunodeficiency virus (HIV) hyperactivates host immune cells, resulting in super-inflammation and acquired immunodeficiency syndrome (AIDS). Cytotoxic derivatives of Ado suppress HIV-1 growth, whereas ADA inactivates cytotoxic nucleosides. ADA inhibition is required to prolong the elimination time and reduce the effective doses of anti-AIDS drugs. Ado levels elevate in the tumour microenvironment, promote immunity suppression and condition tumour cell evasion of immune surveillance. ADA neutralises Ado and restores immunity. Furthermore, ADA can simultaneously bind to the CD26 protein on lymphocytes and the A2AR receptors on antigen-presenting dendritic cells. Created CD26-ADA-A2AR complex bridges T and dendritic cells, stimulating T lymphocyte function.
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Drug Discovery Landscape
6 orphan drug designations for Severe combined immunodeficiency due to adenosine deaminase deficiency, including 3 approved therapies.
6 orphan drug designations for Severe combined immunodeficiency due to adenosine deaminase deficiency, including 3 approved therapies.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
elapegademase-lvlr [Revcovi] | proteins | FDA | 2015-03-19 | 2018-10-05 | Chiesi USA Inc. |
autologous bone marrow CD34+ cells transduced ex vivo with a self activating HIV-1 -based lentiviral vector, EFS-ADA | gene therapies | FDA | 2014-10-21 | — | Donald B. Kohn, M.D. |
Autologous CD34+ cells transduced with a lentiviral vector containing the human ADA gene | gene therapies | EMA | 2013-06-07 | — | AdRes EU B.V. |
autologus CD34+ cells transfected with retroviral vector containing adenosine deaminase gene | gene therapies | FDA | 2009-08-26 | — | Fondazione Telethon ETS |
Autologous CD34+ cells transfected with retroviral vector containing adenosine deaminase gene [Strimvelis] | gene therapies | EMA | 2005-08-26 | 2016-05-30 | Fondazione Telethon Ets |
Pegademase bovine [Adagen] | proteins | FDA | 1984-05-29 | 1990-03-21 | Sigma-tau Pharmaceuticals, Inc. |
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