RARE DISEASE
Severe combined immunodeficiency due to DCLRE1C deficiency
Severe combined immunodeficiency due to DCLRE1C deficiency
Severe combined immunodeficiency due to DCLRE1C deficiency
Synonyms: SCID due to ARTEMIS deficiency, SCID due to DCLRE1C deficiency, SCID, Athabascan type, SCID, Athabaskan type, Severe combined immunodeficiency due to ARTEMIS deficiency, Severe combined immunodeficiency, Athabascan type, Severe combined immunodeficiency, Athabaskan type
Synonyms: SCID due to ARTEMIS deficiency, SCID due to DCLRE1C deficiency, SCID, Athabascan type, SCID, Athabaskan type, Severe combined immunodeficiency due to ARTEMIS deficiency, Severe combined immunodeficiency, Athabascan type, Severe combined immunodeficiency, Athabaskan type
Synonyms: SCID due to ARTEMIS deficiency, SCID due to DCLRE1C deficiency, SCID, Athabascan type, SCID, Athabaskan type, Severe combined immunodeficiency due to ARTEMIS deficiency, Severe combined immunodeficiency, Athabascan type, Severe combined immunodeficiency, Athabaskan type
Drug discovery
3
drugs
With orphan designations
Overview
Severe combined immunodeficiency due to DCLRE1C deficiency (Artemis deficiency) is a rare autosomal recessive disorder characterized by T-B-NK+ immunodeficiency, radiosensitivity, and severe infections starting in infancy. Patients exhibit failure to thrive, chronic diarrhea, and susceptibility to opportunistic pathogens. Immunologically, T and B cells are absent or profoundly reduced, while NK cells remain normal. Early hematopoietic stem cell transplantation (HSCT) is curative but requires radiation-free conditioning due to defective DNA repair mechanisms [1][3][7].
Burden
Mortality exceeds 50% without HSCT, often due to infections or graft failure [1][3].
Post-HSCT complications include chronic lung disease (bronchiectasis, fibrosis) and autoimmune manifestations [2][12].
Delayed diagnosis (median: 2 months) increases pre-transplant morbidity and resource utilization [1][7].
Therapies
HSCT with reduced-toxicity conditioning (e.g., treosulfan/fludarabine) achieves survival rates >70% when performed early [1][10].
Pre-transplant management includes immunoglobulin replacement, antimicrobial prophylaxis, and nutritional support [1][3].
Gene therapy remains experimental but shows promise in preclinical models [10].
Categories: rare genetic diseases, rare immunological diseases, rare transplant-related disorders
Research Papers
84 drug discovery papers about Severe combined immunodeficiency due to DCLRE1C deficiency. Recent publications:
84 drug discovery papers about Severe combined immunodeficiency due to DCLRE1C deficiency. Recent publications:
categories:
Small molecules
cell therapies
2025-11-25 | Outcomes following matched sibling donor transplantation for severe combined immunodeficiency: a report from the PIDTC.
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.
2023-10-12 | A novel splice donor mutation in DCLRE1C caused atypical severe combined immunodeficiency in a patient with colon lymphoma: case report and literature review
Hypomorphic mutations of DCLRE1C cause an atypical severe combined immunodeficiency (SCID), and Epstein-Barr virus (EBV)-related colon lymphoma is a rare complication.A teenage boy presented with colon EBV-related colon lymphoma, plantar warts, and a history of recurrent pneumonia. His peripheral blood lymphocyte count and serum level of immunoglobulin (Ig) G were normal, but he exhibited a T+B-NK+ immunophenotype. Genetic analysis by whole exome sequencing revealed compound heterozygous mutations of DCLRE1C (NM_001033855.3), including a novel paternal splicing donor mutation (c.109 + 2T>C) in intron 1, and a maternal c.1147C>T (p.R383X) nonsense mutation in exon 13. Based on his clinical features and genetic results, the diagnosis of atypical SCID with colon lymphoma was established. Our review shows that seven patients, including our patient, have been reported to develop lymphoma, all with hypomorphic DCLRE1C mutations. Among these cases, six had EBV-related B-cell lineage lymphoma, and one had Hodgkin lymphoma with EBV reactivation. Unfortunately, all of the patients died.Recognizing the radiosensitivity of the disease is critical for the prognosis. Hematopoietic stem cell transplantation before being infected with EBV is an optimal treatment.
2023-06-20 | Measuring the effect of newborn screening on survival after haematopoietic cell transplantation for severe combined immunodeficiency: a 36-year longitudinal study from the Primary Immune Deficiency Treatment Consortium
Background Severe combined immunodeficiency (SCID) is fatal unless durable adaptive immunity is established, most commonly through allogeneic haematopoietic cell transplantation (HCT). The Primary Immune Deficiency Treatment Consortium (PIDTC) explored factors affecting the survival of individuals with SCID over almost four decades, focusing on the effects of population-based newborn screening for SCID that was initiated in 2008 and expanded during 2010–18. Methods We analysed transplantation-related data from children with SCID treated at 34 PIDTC sites in the USA and Canada, using the calendar time intervals 1982–89, 1990–99, 2000–09, and 2010–18. Categorical variables were compared by χ2 test and continuous outcomes by the Kruskal-Wallis test. Overall survival was estimated by the Kaplan-Meier method. A multivariable analysis using Cox proportional hazards regression models examined risk factors for HCT outcomes, including the variables of time interval of HCT, infection status and age at HCT, trigger for diagnosis, SCID type and genotype, race and ethnicity of the patient, non-HLA-matched sibling donor type, graft type, GVHD prophylaxis, and conditioning intensity. Findings For 902 children with confirmed SCID, 5-year overall survival remained unchanged at 72%–73% for 28 years until 2010–18, when it increased to 87% (95% CI 82·1–90·6; n=268; p=0·0005). For children identified as having SCID by newborn screening since 2010, 5-year overall survival was 92·5% (95% CI 85·8–96·1), better than that of children identified by clinical illness or family history in the same interval (79·9% [69·5–87·0] and 85·4% [71·8–92·8], respectively [p=0·043]). Multivariable analysis demonstrated that the factors of active infection (hazard ratio [HR] 2·41, 95% CI 1·56–3·72; p<0·0001), age 3·5 months or older at HCT (2·12, 1·38–3·24; p=0·001), Black or African-American race (2·33, 1·56–3·46; p<0·0001), and certain SCID genotypes to be associated with lower overall survival during all time intervals. Moreover, after adjusting for several factors in this multivariable analysis, HCT after 2010 no longer conveyed a survival advantage over earlier time intervals studied (HR 0·73, 95% CI 0·43–1·26; p=0·097). This indicated that younger age and freedom from infections at HCT, both directly driven by newborn screening, were the main drivers for recent improvement in overall survival. Interpretation Population-based newborn screening has facilitated the identification of infants with SCID early in life, in turn leading to prompt HCT while avoiding infections. Public health programmes worldwide can benefit from this definitive demonstration of the value of newborn screening for SCID. Funding National Institute of Allergy and Infectious Diseases, Office of Rare Diseases Research, and National Center for Advancing Translational Sciences.
2023-02-28 | Successful TCRαβ/CD19-Depleted Hematopoietic Cell Transplantation for a Patient With Artemis Deficiency.
Artemis deficiency is characterized by DNA double-strand breaks repairing dysfunction and increased sensitivity to ionizing radiation and alkylating reagents. We describe the first successful case of T-cell receptor [TCR]αβ/CD19-depleted hematopoietic cell transplantation [HCT] for Artemis deficiency in Japan. A 6-month-old Korean boy was diagnosed with Artemis-deficient severe combined immunodeficiency. He had no human leukocyte antigen (HLA)-matched sibling or unrelated donor. Therefore, TCRαβ/CD19-depleted HCT from his haploidentical mother was performed. Despite mixed chimerism in whole blood, T cells achieved complete donor chimerism 6 months after HCT. TCRαβ/CD19-depleted HCT could be an effective treatment for patients with radiation-sensitive severe combined immunodeficiency.
2022-10-14 | Allogeneic and xenogeneic lymphoid reconstitution in a RAG2−/−IL2RGy/− severe combined immunodeficient pig: A preclinical model for intrauterine hematopoietic transplantation
Mice with severe combined immunodeficiency are commonly used as hosts of human cells. Size, longevity, and physiology, however, limit the extent to which immunodeficient mice can model human systems. To address these limitations, we generated RAG2-/-IL2RGy/- immunodeficient pigs and demonstrate successful engraftment of SLA mismatched allogeneic D42 fetal liver cells, tagged with pH2B-eGFP, and human CD34+ hematopoietic stem cells after in utero cell transplantation. Following intrauterine injection at day 42-45 of gestation, fetuses were allowed to gestate to term and analyzed postnatally for the presence of pig (allogeneic) and human (xenogeneic) B cells, T-cells and NK cells in peripheral blood and other lymphoid tissues. Engraftment of allogeneic hematopoietic cells was detected based on co-expression of pH2B-eGFP and various markers of differentiation. Analysis of spleen revealed robust generation and engraftment of pH2B-eGFP mature B cells (and IgH recombination) and mature T-cells (and TCR-β recombination), T helper (CD3+CD4+) and T cytotoxic (CD3+CD8+) cells. The thymus revealed engraftment of pH2B-eGFP double negative precursors (CD4-CD8-) as well as double positive (CD4+, CD8+) precursors and single positive T-cells. After intrauterine administration of human CD34+ hematopoietic stem cells, analysis of peripheral blood and lymphoid tissues revealed the presence of human T-cells (CD3+CD4+ and CD3+CD8+) but no detectable B cells or NK cells. The frequency of human CD45+ cells in the circulation decreased rapidly and were undetectable within 2 weeks of age. The frequency of human CD45+ cells in the spleen also decreased rapidly, becoming undetectable at 3 weeks. In contrast, human CD45+CD3+T-cells comprised >70% of cells in the pig thymus at birth and persisted at the same frequency at 3 weeks. Most human CD3+ cells in the pig's thymus expressed CD4 or CD8, but few cells were double positive (CD4+ CD8+). In addition, human CD3+ cells in the pig thymus contained human T-cell excision circles (TREC), suggesting de novo development. Our data shows that the pig thymus provides a microenvironment conducive to engraftment, survival and development of human T-cells and provide evidence that the developing T-cell compartment can be populated to a significant extent by human cells in large animals.
small molecules
2022-07-25 | Structural analysis of the basal state of the Artemis:DNA-PKcs complex.
Artemis nuclease and DNA-dependent protein kinase catalytic subunit (DNA-PKcs) are key components in nonhomologous DNA end joining (NHEJ), the major repair mechanism for double-strand DNA breaks. Artemis activation by DNA-PKcs resolves hairpin DNA ends formed during V(D)J recombination. Artemis deficiency disrupts development of adaptive immunity and leads to radiosensitive T- B- severe combined immunodeficiency (RS-SCID). An activated state of Artemis in complex with DNA-PK was solved by cryo-EM recently, which showed Artemis bound to the DNA. Here, we report that the pre-activated form (basal state) of the Artemis:DNA-PKcs complex is stable on an agarose-acrylamide gel system, and suitable for cryo-EM structural analysis. Structures show that the Artemis catalytic domain is dynamically positioned externally to DNA-PKcs prior to ABCDE autophosphorylation and show how both the catalytic and regulatory domains of Artemis interact with the N-HEAT and FAT domains of DNA-PKcs. We define a mutually exclusive binding site for Artemis and XRCC4 on DNA-PKcs and show that an XRCC4 peptide disrupts the Artemis:DNA-PKcs complex. All of the findings are useful in explaining how a hypomorphic L3062R missense mutation of DNA-PKcs could lead to insufficient Artemis activation, hence RS-SCID. Our results provide various target site candidates to design disruptors for Artemis:DNA-PKcs complex formation.
2021-11-04 | Structural and mechanistic insights into the Artemis endonuclease and strategies for its inhibition.
Artemis (SNM1C/DCLRE1C) is an endonuclease that plays a key role in development of B- and T-lymphocytes and in dsDNA break repair by non-homologous end-joining (NHEJ). Artemis is phosphorylated by DNA-PKcs and acts to open DNA hairpin intermediates generated during V(D)J and class-switch recombination. Artemis deficiency leads to congenital radiosensitive severe acquired immune deficiency (RS-SCID). Artemis belongs to a superfamily of nucleases containing metallo-β-lactamase (MBL) and β-CASP (CPSF-Artemis-SNM1-Pso2) domains. We present crystal structures of the catalytic domain of wildtype and variant forms of Artemis, including one causing RS-SCID Omenn syndrome. The catalytic domain of the Artemis has similar endonuclease activity to the phosphorylated full-length protein. Our structures help explain the predominantly endonucleolytic activity of Artemis, which contrasts with the predominantly exonuclease activity of the closely related SNM1A and SNM1B MBL fold nucleases. The structures reveal a second metal binding site in its β-CASP domain unique to Artemis, which is amenable to inhibition by compounds including ebselen. By combining our structural data with that from a recently reported Artemis structure, we were able model the interaction of Artemis with DNA substrates. The structures, including one of Artemis with the cephalosporin ceftriaxone, will help enable the rational development of selective SNM1 nuclease inhibitors.
2020-04-13 | DNA-PKcs chemical inhibition versus genetic mutation: Impact on the junctional repair steps of V(D)J recombination.
Spontaneous DNA-PKcs deficiencies in animals result in a severe combined immunodeficiency (SCID) phenotype because DNA-PKcs is required to activate Artemis for V(D)J recombination coding end hairpin opening. The impact on signal joint formation in these spontaneous mutant mammals is variable. Genetically engineered DNA-PKcs null mice and cells from them show a >1,000-fold reduction in coding joint formation and minimal reduction in signal joint formation during V(D)J recombination. Does chemical inhibition of DNA-PKcs mimic this phenotype? M3814 (also known as Nedisertib) is a potent DNA-PKcs inhibitor. We find here that M3814 causes a quantitative reduction in coding joint formation relative to signal joint formation. The sequences of signal and coding junctions were within normal limits, though rare coding joints showed novel features. The signal junctions generally did not show evidence of resection into the signal ends that is often seen in cells that have genetic defects in DNA-PKcs. Comparison of the chemical inhibition findings here with the known results for spontaneous and engineered DNA-PKcs mutant mammals is informative for considering pharmacologic small molecule inhibition of DNA-PKcs in various types of neoplasia.
2019-03-12 | Low Exposure Busulfan Conditioning to Achieve Sufficient Multilineage Chimerism in Patients with Severe Combined Immunodeficiency
After allogeneic hematopoietic cell transplantation (HCT), the minimal myeloid chimerism required for full T and B cell reconstitution in patients with severe combined immunodeficiency (SCID) is unknown. We retrospectively reviewed our experience with low-exposure busulfan (cumulative area under the curve, 30 mg·hr/L) in 10 SCID patients undergoing either first or repeat HCT from unrelated or haploidentical donors. The median busulfan dose required to achieve this exposure was 5.9 mg/kg (range, 4.8 to 9.1). With a median follow-up of 4.5 years all patients survived, with 1 requiring an additional HCT. Donor myeloid chimerism was generally >90% at 1 month post-HCT, but in most patients it fell during the next 3 months, such that 1-year median myeloid chimerism was 14% (range, 2% to 100%). Six of 10 patients had full T and B cell reconstitution, despite myeloid chimerism as low as 3%. Three patients have not recovered B cell function at over 2 years post-HCT, 2 of them in the setting of treatment with rituximab for post-HCT autoimmunity. Low-exposure busulfan was well tolerated and achieved sufficient myeloid chimerism for full immune reconstitution in over 50% of patients. However, other factors beyond busulfan exposure may also play critical roles in determining long-term myeloid chimerism and full T and B cell reconstitution.
2016-02-29 | Radiation-sensitive severe combined immunodeficiency: The arguments for and against conditioning before hematopoietic cell transplantation--what to do?
Defects in DNA cross-link repair 1C (DCLRE1C), protein kinase DNA activated catalytic polypeptide (PRKDC), ligase 4 (LIG4), NHEJ1, and NBS1 involving the nonhomologous end-joining (NHEJ) DNA repair pathway result in radiation-sensitive severe combined immunodeficiency (SCID). Results of hematopoietic cell transplantation for radiation-sensitive SCID suggest that minimizing exposure to alkylating agents and ionizing radiation is important for optimizing survival and minimizing late effects. However, use of preconditioning with alkylating agents is associated with a greater likelihood of full T- and B-cell reconstitution compared with no conditioning or immunosuppression alone. A reduced-intensity regimen using fludarabine and low-dose cyclophosphamide might be effective for patients with LIG4, NHEJ1, and NBS1 defects, although more data are needed to confirm these findings and characterize late effects. For patients with mutations in DCLRE1C (Artemis-deficient SCID), there is no optimal approach that uses standard dose-alkylating agents without significant late effects. Until nonchemotherapy agents, such as anti-CD45 or anti-CD117, become available, options include minimizing exposure to alkylators, such as single-agent low-dose targeted busulfan, or achieving T-cell reconstitution, followed several years later with a conditioning regimen to restore B-cell immunity. Gene therapy for these disorders will eventually remove the issues of rejection and graft-versus-host disease. Prospective multicenter studies are needed to evaluate these approaches in this rare but highly vulnerable patient population.
gene therapies
2026-05-15 | Base editing of Artemis mutations ex vivo sheds light on gene therapy for Artemis-deficient SCID.
Artemis is an endonuclease that cleaves DNA hairpins during V(D)J recombination, a critical step enabling coding-joint formation and essential for lymphocyte development. Artemis-deficient severe combined immunodeficiency (ART-SCID) is a monogenic disorder marked by impaired lymphocyte development and poor responsiveness to allogeneic hematopoietic stem cell transplantation. In this study, we explored the use of base editors to correct mutations in the Artemis gene. Specifically, we firstly documented the pathogenic mutations of Artemis from previous studies and newly identified from ClinVar database. Then, we performed ex vivo assays using cytidine base editors (CBEs) to repair the c.181T > C mutation, and adenosine base editors (ABEs) to target the pathogenic c.49G > A and c.404G > A variants associated with ART-SCID. Targeted deep sequencing revealed that rAPOBEC1-SpRY-HF1-BE4max achieved efficient editing (~ 50%) at the c.181T > C site, while ABE8e reached ~ 35% and ~ 20% editing efficiency at the c.49G > A and c.404G > A sites, respectively. Importantly, base editors restored Artemis endonuclease activity in a 293TArtemis-/- system, with no detectable off-target effects at the predicted sites as assessed by targeted deep sequencing. These findings provide proof-of-concept that base editing can correct ART-SCID-associated mutations, highlighting its potential for future therapeutic development.
2017-10-10 | Mutations in XLF/NHEJ1/Cernunnos gene results in downregulation of telomerase genes expression and telomere shortening.
NHEJ1-patients develop severe progressive lymphocytopenia and premature aging of hematopoietic stem cells (HSCs) at a young age. Here we show a patient with a homozygous-NHEJ1 mutation identified by whole exome-sequencing that developed severe pancytopenia and bone marrow aplasia correlating with the presence of short telomeres. The mutation resulted in a truncated protein. In an attempt to identify the mechanism behind the short telomere phenotype found in the NHEJ1-patient we downregulated NHEJ1 expression in 293T and CD34+cells. This downregulation resulted in reduced telomerase activity and decreased expression of several telomerase/shelterin genes. Interestingly, cell lines derived from two other NHEJ1-deficient patients with different mutations also showed increased p21 expression, inhibition in expression of several telomerase complex genes and shortened telomeres. Decrease in expression of telomerase/shelterin genes did not occur when we inhibited expression of other NHEJ genes mutated in SCID patients: DNA-PK, Artemis or LigaseIV. Because premature aging of HSCs is observed only in NHEJ1 patients, we propose that is the result of senescence induced by decreased expression of telomerase/shelterin genes that lead to an inhibition of telomerase activity. Previous reports failed to find this connection because of the use of patient´s cells immortalized by TERT expression or recombined telomeres by ALT pathway. In summary, defective regulation of telomere biology together with defective V(D)J recombination can negatively impact on the evolution of the disease in these patients. Identification of telomere shortening is important since it may open new therapeutic interventions for these patients by treatments aimed to recover the expression of telomerase genes.
cell therapies
2025-11-25 | Outcomes following matched sibling donor transplantation for severe combined immunodeficiency: a report from the PIDTC.
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.
2023-10-12 | A novel splice donor mutation in DCLRE1C caused atypical severe combined immunodeficiency in a patient with colon lymphoma: case report and literature review
Hypomorphic mutations of DCLRE1C cause an atypical severe combined immunodeficiency (SCID), and Epstein-Barr virus (EBV)-related colon lymphoma is a rare complication.A teenage boy presented with colon EBV-related colon lymphoma, plantar warts, and a history of recurrent pneumonia. His peripheral blood lymphocyte count and serum level of immunoglobulin (Ig) G were normal, but he exhibited a T+B-NK+ immunophenotype. Genetic analysis by whole exome sequencing revealed compound heterozygous mutations of DCLRE1C (NM_001033855.3), including a novel paternal splicing donor mutation (c.109 + 2T>C) in intron 1, and a maternal c.1147C>T (p.R383X) nonsense mutation in exon 13. Based on his clinical features and genetic results, the diagnosis of atypical SCID with colon lymphoma was established. Our review shows that seven patients, including our patient, have been reported to develop lymphoma, all with hypomorphic DCLRE1C mutations. Among these cases, six had EBV-related B-cell lineage lymphoma, and one had Hodgkin lymphoma with EBV reactivation. Unfortunately, all of the patients died.Recognizing the radiosensitivity of the disease is critical for the prognosis. Hematopoietic stem cell transplantation before being infected with EBV is an optimal treatment.
2023-06-20 | Measuring the effect of newborn screening on survival after haematopoietic cell transplantation for severe combined immunodeficiency: a 36-year longitudinal study from the Primary Immune Deficiency Treatment Consortium
Background Severe combined immunodeficiency (SCID) is fatal unless durable adaptive immunity is established, most commonly through allogeneic haematopoietic cell transplantation (HCT). The Primary Immune Deficiency Treatment Consortium (PIDTC) explored factors affecting the survival of individuals with SCID over almost four decades, focusing on the effects of population-based newborn screening for SCID that was initiated in 2008 and expanded during 2010–18. Methods We analysed transplantation-related data from children with SCID treated at 34 PIDTC sites in the USA and Canada, using the calendar time intervals 1982–89, 1990–99, 2000–09, and 2010–18. Categorical variables were compared by χ2 test and continuous outcomes by the Kruskal-Wallis test. Overall survival was estimated by the Kaplan-Meier method. A multivariable analysis using Cox proportional hazards regression models examined risk factors for HCT outcomes, including the variables of time interval of HCT, infection status and age at HCT, trigger for diagnosis, SCID type and genotype, race and ethnicity of the patient, non-HLA-matched sibling donor type, graft type, GVHD prophylaxis, and conditioning intensity. Findings For 902 children with confirmed SCID, 5-year overall survival remained unchanged at 72%–73% for 28 years until 2010–18, when it increased to 87% (95% CI 82·1–90·6; n=268; p=0·0005). For children identified as having SCID by newborn screening since 2010, 5-year overall survival was 92·5% (95% CI 85·8–96·1), better than that of children identified by clinical illness or family history in the same interval (79·9% [69·5–87·0] and 85·4% [71·8–92·8], respectively [p=0·043]). Multivariable analysis demonstrated that the factors of active infection (hazard ratio [HR] 2·41, 95% CI 1·56–3·72; p<0·0001), age 3·5 months or older at HCT (2·12, 1·38–3·24; p=0·001), Black or African-American race (2·33, 1·56–3·46; p<0·0001), and certain SCID genotypes to be associated with lower overall survival during all time intervals. Moreover, after adjusting for several factors in this multivariable analysis, HCT after 2010 no longer conveyed a survival advantage over earlier time intervals studied (HR 0·73, 95% CI 0·43–1·26; p=0·097). This indicated that younger age and freedom from infections at HCT, both directly driven by newborn screening, were the main drivers for recent improvement in overall survival. Interpretation Population-based newborn screening has facilitated the identification of infants with SCID early in life, in turn leading to prompt HCT while avoiding infections. Public health programmes worldwide can benefit from this definitive demonstration of the value of newborn screening for SCID. Funding National Institute of Allergy and Infectious Diseases, Office of Rare Diseases Research, and National Center for Advancing Translational Sciences.
2023-02-28 | Successful TCRαβ/CD19-Depleted Hematopoietic Cell Transplantation for a Patient With Artemis Deficiency.
Artemis deficiency is characterized by DNA double-strand breaks repairing dysfunction and increased sensitivity to ionizing radiation and alkylating reagents. We describe the first successful case of T-cell receptor [TCR]αβ/CD19-depleted hematopoietic cell transplantation [HCT] for Artemis deficiency in Japan. A 6-month-old Korean boy was diagnosed with Artemis-deficient severe combined immunodeficiency. He had no human leukocyte antigen (HLA)-matched sibling or unrelated donor. Therefore, TCRαβ/CD19-depleted HCT from his haploidentical mother was performed. Despite mixed chimerism in whole blood, T cells achieved complete donor chimerism 6 months after HCT. TCRαβ/CD19-depleted HCT could be an effective treatment for patients with radiation-sensitive severe combined immunodeficiency.
2022-10-14 | Allogeneic and xenogeneic lymphoid reconstitution in a RAG2−/−IL2RGy/− severe combined immunodeficient pig: A preclinical model for intrauterine hematopoietic transplantation
Mice with severe combined immunodeficiency are commonly used as hosts of human cells. Size, longevity, and physiology, however, limit the extent to which immunodeficient mice can model human systems. To address these limitations, we generated RAG2-/-IL2RGy/- immunodeficient pigs and demonstrate successful engraftment of SLA mismatched allogeneic D42 fetal liver cells, tagged with pH2B-eGFP, and human CD34+ hematopoietic stem cells after in utero cell transplantation. Following intrauterine injection at day 42-45 of gestation, fetuses were allowed to gestate to term and analyzed postnatally for the presence of pig (allogeneic) and human (xenogeneic) B cells, T-cells and NK cells in peripheral blood and other lymphoid tissues. Engraftment of allogeneic hematopoietic cells was detected based on co-expression of pH2B-eGFP and various markers of differentiation. Analysis of spleen revealed robust generation and engraftment of pH2B-eGFP mature B cells (and IgH recombination) and mature T-cells (and TCR-β recombination), T helper (CD3+CD4+) and T cytotoxic (CD3+CD8+) cells. The thymus revealed engraftment of pH2B-eGFP double negative precursors (CD4-CD8-) as well as double positive (CD4+, CD8+) precursors and single positive T-cells. After intrauterine administration of human CD34+ hematopoietic stem cells, analysis of peripheral blood and lymphoid tissues revealed the presence of human T-cells (CD3+CD4+ and CD3+CD8+) but no detectable B cells or NK cells. The frequency of human CD45+ cells in the circulation decreased rapidly and were undetectable within 2 weeks of age. The frequency of human CD45+ cells in the spleen also decreased rapidly, becoming undetectable at 3 weeks. In contrast, human CD45+CD3+T-cells comprised >70% of cells in the pig thymus at birth and persisted at the same frequency at 3 weeks. Most human CD3+ cells in the pig's thymus expressed CD4 or CD8, but few cells were double positive (CD4+ CD8+). In addition, human CD3+ cells in the pig thymus contained human T-cell excision circles (TREC), suggesting de novo development. Our data shows that the pig thymus provides a microenvironment conducive to engraftment, survival and development of human T-cells and provide evidence that the developing T-cell compartment can be populated to a significant extent by human cells in large animals.
small molecules
2022-07-25 | Structural analysis of the basal state of the Artemis:DNA-PKcs complex.
Artemis nuclease and DNA-dependent protein kinase catalytic subunit (DNA-PKcs) are key components in nonhomologous DNA end joining (NHEJ), the major repair mechanism for double-strand DNA breaks. Artemis activation by DNA-PKcs resolves hairpin DNA ends formed during V(D)J recombination. Artemis deficiency disrupts development of adaptive immunity and leads to radiosensitive T- B- severe combined immunodeficiency (RS-SCID). An activated state of Artemis in complex with DNA-PK was solved by cryo-EM recently, which showed Artemis bound to the DNA. Here, we report that the pre-activated form (basal state) of the Artemis:DNA-PKcs complex is stable on an agarose-acrylamide gel system, and suitable for cryo-EM structural analysis. Structures show that the Artemis catalytic domain is dynamically positioned externally to DNA-PKcs prior to ABCDE autophosphorylation and show how both the catalytic and regulatory domains of Artemis interact with the N-HEAT and FAT domains of DNA-PKcs. We define a mutually exclusive binding site for Artemis and XRCC4 on DNA-PKcs and show that an XRCC4 peptide disrupts the Artemis:DNA-PKcs complex. All of the findings are useful in explaining how a hypomorphic L3062R missense mutation of DNA-PKcs could lead to insufficient Artemis activation, hence RS-SCID. Our results provide various target site candidates to design disruptors for Artemis:DNA-PKcs complex formation.
2021-11-04 | Structural and mechanistic insights into the Artemis endonuclease and strategies for its inhibition.
Artemis (SNM1C/DCLRE1C) is an endonuclease that plays a key role in development of B- and T-lymphocytes and in dsDNA break repair by non-homologous end-joining (NHEJ). Artemis is phosphorylated by DNA-PKcs and acts to open DNA hairpin intermediates generated during V(D)J and class-switch recombination. Artemis deficiency leads to congenital radiosensitive severe acquired immune deficiency (RS-SCID). Artemis belongs to a superfamily of nucleases containing metallo-β-lactamase (MBL) and β-CASP (CPSF-Artemis-SNM1-Pso2) domains. We present crystal structures of the catalytic domain of wildtype and variant forms of Artemis, including one causing RS-SCID Omenn syndrome. The catalytic domain of the Artemis has similar endonuclease activity to the phosphorylated full-length protein. Our structures help explain the predominantly endonucleolytic activity of Artemis, which contrasts with the predominantly exonuclease activity of the closely related SNM1A and SNM1B MBL fold nucleases. The structures reveal a second metal binding site in its β-CASP domain unique to Artemis, which is amenable to inhibition by compounds including ebselen. By combining our structural data with that from a recently reported Artemis structure, we were able model the interaction of Artemis with DNA substrates. The structures, including one of Artemis with the cephalosporin ceftriaxone, will help enable the rational development of selective SNM1 nuclease inhibitors.
2020-04-13 | DNA-PKcs chemical inhibition versus genetic mutation: Impact on the junctional repair steps of V(D)J recombination.
Spontaneous DNA-PKcs deficiencies in animals result in a severe combined immunodeficiency (SCID) phenotype because DNA-PKcs is required to activate Artemis for V(D)J recombination coding end hairpin opening. The impact on signal joint formation in these spontaneous mutant mammals is variable. Genetically engineered DNA-PKcs null mice and cells from them show a >1,000-fold reduction in coding joint formation and minimal reduction in signal joint formation during V(D)J recombination. Does chemical inhibition of DNA-PKcs mimic this phenotype? M3814 (also known as Nedisertib) is a potent DNA-PKcs inhibitor. We find here that M3814 causes a quantitative reduction in coding joint formation relative to signal joint formation. The sequences of signal and coding junctions were within normal limits, though rare coding joints showed novel features. The signal junctions generally did not show evidence of resection into the signal ends that is often seen in cells that have genetic defects in DNA-PKcs. Comparison of the chemical inhibition findings here with the known results for spontaneous and engineered DNA-PKcs mutant mammals is informative for considering pharmacologic small molecule inhibition of DNA-PKcs in various types of neoplasia.
2019-03-12 | Low Exposure Busulfan Conditioning to Achieve Sufficient Multilineage Chimerism in Patients with Severe Combined Immunodeficiency
After allogeneic hematopoietic cell transplantation (HCT), the minimal myeloid chimerism required for full T and B cell reconstitution in patients with severe combined immunodeficiency (SCID) is unknown. We retrospectively reviewed our experience with low-exposure busulfan (cumulative area under the curve, 30 mg·hr/L) in 10 SCID patients undergoing either first or repeat HCT from unrelated or haploidentical donors. The median busulfan dose required to achieve this exposure was 5.9 mg/kg (range, 4.8 to 9.1). With a median follow-up of 4.5 years all patients survived, with 1 requiring an additional HCT. Donor myeloid chimerism was generally >90% at 1 month post-HCT, but in most patients it fell during the next 3 months, such that 1-year median myeloid chimerism was 14% (range, 2% to 100%). Six of 10 patients had full T and B cell reconstitution, despite myeloid chimerism as low as 3%. Three patients have not recovered B cell function at over 2 years post-HCT, 2 of them in the setting of treatment with rituximab for post-HCT autoimmunity. Low-exposure busulfan was well tolerated and achieved sufficient myeloid chimerism for full immune reconstitution in over 50% of patients. However, other factors beyond busulfan exposure may also play critical roles in determining long-term myeloid chimerism and full T and B cell reconstitution.
2016-02-29 | Radiation-sensitive severe combined immunodeficiency: The arguments for and against conditioning before hematopoietic cell transplantation--what to do?
Defects in DNA cross-link repair 1C (DCLRE1C), protein kinase DNA activated catalytic polypeptide (PRKDC), ligase 4 (LIG4), NHEJ1, and NBS1 involving the nonhomologous end-joining (NHEJ) DNA repair pathway result in radiation-sensitive severe combined immunodeficiency (SCID). Results of hematopoietic cell transplantation for radiation-sensitive SCID suggest that minimizing exposure to alkylating agents and ionizing radiation is important for optimizing survival and minimizing late effects. However, use of preconditioning with alkylating agents is associated with a greater likelihood of full T- and B-cell reconstitution compared with no conditioning or immunosuppression alone. A reduced-intensity regimen using fludarabine and low-dose cyclophosphamide might be effective for patients with LIG4, NHEJ1, and NBS1 defects, although more data are needed to confirm these findings and characterize late effects. For patients with mutations in DCLRE1C (Artemis-deficient SCID), there is no optimal approach that uses standard dose-alkylating agents without significant late effects. Until nonchemotherapy agents, such as anti-CD45 or anti-CD117, become available, options include minimizing exposure to alkylators, such as single-agent low-dose targeted busulfan, or achieving T-cell reconstitution, followed several years later with a conditioning regimen to restore B-cell immunity. Gene therapy for these disorders will eventually remove the issues of rejection and graft-versus-host disease. Prospective multicenter studies are needed to evaluate these approaches in this rare but highly vulnerable patient population.
gene therapies
2026-05-15 | Base editing of Artemis mutations ex vivo sheds light on gene therapy for Artemis-deficient SCID.
Artemis is an endonuclease that cleaves DNA hairpins during V(D)J recombination, a critical step enabling coding-joint formation and essential for lymphocyte development. Artemis-deficient severe combined immunodeficiency (ART-SCID) is a monogenic disorder marked by impaired lymphocyte development and poor responsiveness to allogeneic hematopoietic stem cell transplantation. In this study, we explored the use of base editors to correct mutations in the Artemis gene. Specifically, we firstly documented the pathogenic mutations of Artemis from previous studies and newly identified from ClinVar database. Then, we performed ex vivo assays using cytidine base editors (CBEs) to repair the c.181T > C mutation, and adenosine base editors (ABEs) to target the pathogenic c.49G > A and c.404G > A variants associated with ART-SCID. Targeted deep sequencing revealed that rAPOBEC1-SpRY-HF1-BE4max achieved efficient editing (~ 50%) at the c.181T > C site, while ABE8e reached ~ 35% and ~ 20% editing efficiency at the c.49G > A and c.404G > A sites, respectively. Importantly, base editors restored Artemis endonuclease activity in a 293TArtemis-/- system, with no detectable off-target effects at the predicted sites as assessed by targeted deep sequencing. These findings provide proof-of-concept that base editing can correct ART-SCID-associated mutations, highlighting its potential for future therapeutic development.
2017-10-10 | Mutations in XLF/NHEJ1/Cernunnos gene results in downregulation of telomerase genes expression and telomere shortening.
NHEJ1-patients develop severe progressive lymphocytopenia and premature aging of hematopoietic stem cells (HSCs) at a young age. Here we show a patient with a homozygous-NHEJ1 mutation identified by whole exome-sequencing that developed severe pancytopenia and bone marrow aplasia correlating with the presence of short telomeres. The mutation resulted in a truncated protein. In an attempt to identify the mechanism behind the short telomere phenotype found in the NHEJ1-patient we downregulated NHEJ1 expression in 293T and CD34+cells. This downregulation resulted in reduced telomerase activity and decreased expression of several telomerase/shelterin genes. Interestingly, cell lines derived from two other NHEJ1-deficient patients with different mutations also showed increased p21 expression, inhibition in expression of several telomerase complex genes and shortened telomeres. Decrease in expression of telomerase/shelterin genes did not occur when we inhibited expression of other NHEJ genes mutated in SCID patients: DNA-PK, Artemis or LigaseIV. Because premature aging of HSCs is observed only in NHEJ1 patients, we propose that is the result of senescence induced by decreased expression of telomerase/shelterin genes that lead to an inhibition of telomerase activity. Previous reports failed to find this connection because of the use of patient´s cells immortalized by TERT expression or recombined telomeres by ALT pathway. In summary, defective regulation of telomere biology together with defective V(D)J recombination can negatively impact on the evolution of the disease in these patients. Identification of telomere shortening is important since it may open new therapeutic interventions for these patients by treatments aimed to recover the expression of telomerase genes.
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Drug Discovery Landscape
3 orphan drug designations for Severe combined immunodeficiency due to DCLRE1C deficiency.
3 orphan drug designations for Severe combined immunodeficiency due to DCLRE1C deficiency.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
Autologous CD34+ haematopoietic stem and progenitor cells transduced with a lentiviral vector containing the human DCLRE1C gene | gene therapies | EMA | Assistance Publique Hopitaux De Paris | |
autologous CD34+ cells transduced with a lentiviral vector containing the human RAG1 gene | gene therapies | FDA | Videja B.V. | |
autologous CD34+ hematopoietic stem and progenitor cells transduced with lentiviral vector containing the human DCLRE1C complementary DNA | gene therapies | FDA | — | Morton J Cowan, M.D. |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
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