RARE DISEASE
Congenital dyserythropoietic anemia
Congenital dyserythropoietic anemia
Congenital dyserythropoietic anemia
Synonyms: CDA
Synonyms: CDA
Synonyms: CDA
Drug discovery
0
drugs
With orphan designations
Overview
Congenital dyserythropoietic anemia (CDA) comprises rare inherited disorders of ineffective erythropoiesis, characterized by defective red blood cell maturation, anemia, and morphological bone marrow abnormalities (e.g., bi-/multinucleated erythroblasts). Subtypes I–IV are linked to distinct genetic mutations (CDAN1, SEC23B, KIF23/RACGAP1, KLF1), with overlapping features including jaundice, hepatosplenomegaly, and secondary iron overload. Diagnosis combines clinical evaluation, bone marrow analysis, and genetic testing [1][4][5].
Burden
Therapies
Supportive care: Transfusions (severe anemia), iron chelation (deferasirox/deferiprone) for overload [3][12][16].
Targeted interventions: Interferon-α improves anemia in CDA I [8][19]; splenectomy reduces hemolysis [3][12].
Curative options: Hematopoietic stem cell transplantation (HSCT) for transfusion-dependent cases [11][12]; experimental gene therapy (lentiviral SEC23B correction in CDA II) [7][15].
Categories: rare genetic diseases, rare hematological diseases
Research Papers
138 drug discovery papers about Congenital dyserythropoietic anemia, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
138 drug discovery papers about Congenital dyserythropoietic anemia, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-07-28 | Case Report: HCV-triggered porphyria cutanea tarda in a patient with SEC23B-mutated congenital dyserythropoietic anemia type II.
Porphyria cutanea tarda (PCT) is a hepatic porphyria often triggered by hepatitis C virus (HCV) infection, iron overload, or environmental exposure. Congenital dyserythropoietic anemia type II (CDA II) caused by SEC23B mutations leads to ineffective erythropoiesis and secondary iron accumulation. We report a 34-year-old man with genetically confirmed SEC23B-mutated CDA II who developed photosensitive bullae associated with chronic HCV genotype 1b infection, hyperbilirubinemia, and severe iron overload. Urinary porphyrins were positive, and skin biopsy showed subepidermal bullae with PAS-positive deposits, supporting the diagnosis of PCT. After unsuccessful therapy with hydroxychloroquine, treatment with sofosbuvir/velpatasvir achieved sustained virologic response, resolution of skin lesions, and marked ferritin reduction. This case illustrates that viral and metabolic stressors can trigger PCT in CDA II patients with possible hepatic involvement, underscoring the importance of recognizing combined genetic and infectious factors in rare hematologic disorders.
2026-05-25 | KIF23 in disease pathogenesis and its therapeutic and diagnostic potential.
Kinesin family member 23 (KIF23) is a microtubule-dependent motor protein essential for cytokinesis, organelle transport, and signaling pathway regulation. Its dysregulation contributes to both tumorigenesis and non-malignant disorders; however, a comprehensive review integrating recent mechanistic and translational insights is currently lacking. A literature search across PubMed, Web of Science, Embase, and public databases (such as TCGA), using keywords including "KIF23," "MKLP1," and "cytokinesis" was performed. Published bioinformatic findings, including pan cancer screening and machine learning analyses, linking KIF23 to disease pathogenesis were summarized. KIF23 is frequently upregulated in various cancers, such as colorectal, gastric, hepatocellular and breast cancer, where it activates key oncogenic pathways including Wnt/β-catenin, PI3K-Akt and NF-κB. It remodels the tumor immune microenvironment and correlates with poor prognosis. In contrast, loss-of-function mutations in KIF23 underlie several non-neoplastic diseases, such as congenital dyserythropoietic anemia type III and primary microcephaly, by causing cytokinesis failure and developmental defects. KIF23 expression is regulated through multilayered networks involving transcriptional, epigenetic and competing endogenous RNA (ceRNA) mechanisms. Preclinical studies underscore its potential as a diagnostic biomarker and a promising therapeutic target. KIF23 plays a context-dependent, dual role in disease pathogenesis and represents a compelling target for precision medicine. Future research should focus on deciphering the functional heterogeneity of its splice variants, developing tumor-selective inhibitors and validating integrated biomarker panels to advance clinical translation.
2026-01-12 | Use of Post-Transplant Cyclophosphamide in Matched Related and Unrelated Donor Hematopoietic Stem Cell Transplant for Benign Hematological Disorders.
Introduction of Post-Transplant Cyclophosphamide (PTCy) based immunosuppression in Haploidentical Hematopoietic Stem Cell Transplants (HSCT) has shown to reduce the incidence of Graft vs. Host Disease (GVHD). However, data on its use in HLA matched settings is lacking. We describe our experience using PTCY in pediatric patients undergoing matched donor HSCT. We retrospectively analysed data of 16 patients who underwent HLA-matched HSCT using PTCy from March 2022-July 2024 at our institute. Sixteen patients of median age-6 years (Range:1-17 years) were analysed. Indications of transplant were Thalassemia in 10, severe aplastic anemia in 5 and Congenital dyserythropoietic anemia in 1. Conditioning regimes used were Rabbit ATG-Thio-Flu-Cy-2 Gy TBI in 8 and Rabbit ATG-Thio-Treo-Flu-2 Gy TBI in 3 which was preceded by two cycles of pre-transplant immunosuppression (PTIS); Rabbit ATG-Flu-Cy-4 Gy TBI in 5 patients of aplastic anemia. PTCy, Mycophenolate mofetil and cyclosporine were used as GVHD prophylaxis. One patient had primary and another had CMV induced secondary graft failure. Three patients had grade I-II acute GVHD at median 32days post HSCT (Range: 28-140days). None of the patients had chronic GVHD. CMV reactivation occurred in 8 patients at a median + 21 days (Range: 14-35 days). Median follow up duration post HSCT was 473days (Range:85-808 days). 1 year- Event-free and 1 year-overall survival rates were 81.25% and 93.7% respectively. PTCy-based approach appears to be promising in matched related and unrelated donor transplants for benign hematological disorders.
2025-05-24 | Angioid streaks and optic disc drusen in a patient with congenital dyserythropoietic anaemia.
A man in his 60s with dry eye symptoms was noted to have angioid streaks under the peripapillary retina. Congenital dyserythropoietic anaemia was the major health issue throughout his life, requiring venesection for iron overload, but no transfusions for many years. Close inspection of the eyes with optical coherence tomography also detected small subclinical optic disc drusen, which have not been reported in association with congenital dyserythropoietic anaemia. Together, optic disc drusen and angioid streaks represent an ectopic calcification phenotype in the eye and can be seen in the more common inherited condition of pseudoxanthoma elasticum or other inherited haemolytic anaemias such as sickle cell or thalassaemia. These associations highlight the role of pyrophosphate as a physiological inhibitor of calcification, and deficiencies of serum pyrophosphate lead to excessive and ectopic calcification. This raises intriguing hypotheses for the treatment of optic disc drusen, angioid streaks and other conditions of ectopic calcification.
2024-08-03 | Use Of Post Transplant Cyclophosphamide In Matched Related And Unrelated Donor Hematopoietic Stem Cell Transplant For Benign Hematological Disorders
Background: Introduction of Post-Transplant Cyclophosphamide (PTCy) based immunosuppression in Haploidentical Hematopoietic Stem Cell Transplants (HSCT) has shown to reduce the incidence of Graft vs Host Disease (GVHD). However, data on its use in HLA matched settings is lacking. Here we describe our experience using PTCY in pediatric patients undergoing HSCT for the same. Methods: We retrospectively analysed data of 16 pediatric patients who underwent HLA matched HSCT using PTCy from March 2022 to November 2023 at our institute. Results: Sixteen patients of median age-6 years (Range: 1 to 17 years) were analysed. Male: female ratio was 3.3:1. Indications of transplant were Thalassemia major in 10, severe aplastic anemia in 5 and Congenital dyserythropoietic anemia type II in 1. Conditioning regimes used were Rabbit ATG-Thio-Flu-Cy-2Gy TBI in 8 and Rabbit ATG-Thio-Treo-Flu-2Gy TBI in 3 which was preceded by two cycles of pre-transplant immunosuppression (PTIS); Rabbit ATG-Flu-Cy-4Gy TBI in 5 patients. Median CD34 dose was 5.1 million/kg (Range: 4.7 to 5.6 million/kg). PTCy (50 mg/kg on d+3, +4), Mycophenolate mofetil and cyclosporine were used as GVHD prophylaxis. Fifteen patients had neutrophil enlargement at median 16 days (Range:11- 21 days). One patient had primary and one had secondary graft failure. Cytomegalovirus reactivation was seen in 8 patients. Of the 14 evaluable patients, 3 patients had grade I-II acute GVHD at median 32 days post HSCT (Range: 28-140days). None of the patients had chronic GVHD. Median follow up duration post HSCT was 473 days (Range: 85-808 days). Event free and overall survival rates were 81.25% and 93.7% respectively. Conclusion: PTCy based approach appears to be promising in matched related and unrelated donor transplants for benign hematological disorders.
proteins
2026-08-04 | Identification of a Novel Compound Heterozygous SEC23B in a Chinese Child with Congenital Dyserythropoietic Anemia Type II.
Congenital dyserythropoietic anemia type II (CDA II) is a rare hyporegenerative inherited anemia, resulting from a mutation in SEC23B. In the present case, our patient exhibited moderate anemia, jaundice, hepatosplenomegaly, tea-colored urine, hyperbilirubinemia, and iron overload. Whole exome sequencing revealed that the patient carried a compound heterozygous genotype in SEC23B consisting of a previously unreported missense variant c.181T > C (p.C61R) and a known pathogenic variant c.1832G > A (p.R611Q). Bone marrow aspirate demonstrated erythroid hyperplasia with abnormal erythroblast morphology. Bioinformatic analysis predicted the protein structures, indicating that p.C61R and p.R611Q mutations induce structural changes in their surrounding regions. SEC23B mRNA and protein levels in peripheral blood mononuclear cells (PBMCs) were significantly reduced compared with those in normal control cells, supporting their pathogenicity. Accordingly, a diagnosis of CDA II was considered. In this study, we identified a compound heterozygous SEC23B genotype in the patient and demonstrated that missense mutations of p.C61R and p.R611Q resulted in reduced levels of SEC23B mRNA and protein, suggesting the association of this genotype with CDA II.
2026-02-09 | Additive effect of multiple genetic variants in SEC23B and PIEZO1 on iron metabolism dyshomeostasis in hereditary anemias.
Hereditary anemias encompass a genetically heterogeneous spectrum of disorders, often involving multi-locus inheritance, which can complicate clinical management and worsen disease severity. This study investigates the impact of the co-inheritance of SEC23B loss-of-function pathogenic variants, which lead to congenital dyserythropoietic anemia type II (CDA II), and PIEZO1 gain-of-function pathogenic variants, associated with dehydrated hereditary stomatocytosis type I (DHS1), on hematological parameters and iron metabolism. Among 583 patients with suspected hereditary anemia, 13 were found to carry both SEC23B and PIEZO1 variants, leading to a dual diagnosis of CDA II and DHS1. Compared to those with isolated CDA II, these patients exhibited a significantly higher absolute reticulocyte count and bone marrow responsiveness index, alongside an increased prevalence of elevated ferritin levels. Functional studies in Hep3B human hepatoma cells confirmed that SEC23B knockdown combined with PIEZO1 gain-of-function led to marked ferritin accumulation and reduced hepcidin expression, driven by altered BMP/SMAD signaling and ERK1/2 MAPK pathway. These findings demonstrate how multi-locus inheritance can modify disease severity, particularly by exacerbating iron overload. Our results underscore the clinical relevance of comprehensive genetic testing for enhanced risk stratification and personalized management of hereditary anemias.
2026-01-29 | Anemia-associated mutations disrupt the CDIN1-Codanin1 complex in inherited congenital dyserythropoietic anemia I (CDA-I) disease.
Congenital dyserythropoietic anemia type I (CDA-I) is a rare hereditary disease marked by ineffective erythropoiesis, a characteristic spongy heterochromatin structure in erythroblasts, and mutations in the genes CDAN1 and CDIN1, which encode the proteins Codanin1 and CDIN1. Codanin1 regulates histone shuttling via the chaperone ASF1, yet the role of CDIN1 in CDA-I pathology remains unclear. Notably, CDIN1 is known to interact directly with the C-terminus of Codanin1. Although mutations in both genes are critical to the disease phenotype, their molecular-level effects have not been fully elucidated. Here, we present a comprehensive structural and functional analysis of the CDIN1-Codanin1 C-terminus complex. Using complementary biophysical techniques, we show that CDIN1 and Codanin1 C-terminus form a high-affinity heterodimeric complex with equimolar stoichiometry. We further delineate the essential interacting regions of CDIN1 and Codanin1. We demonstrate that CDA-I-associated mutations in either protein disrupt the CDIN1-Codanin1 interaction, suggesting a potential molecular mechanism underlying the disease.
2026-01-28 | Using Patient Feedback to Improve Treatment Outcomes for Patients with Congenital Dyserythropoietic Anaemia Type I Receiving Interferon Therapy.
Congenital dyserythropoietic anaemia type-I (CDA-I) is a rare autosomal recessive disease characterised by ineffective erythropoiesis, haemolysis and non-haematological developmental abnormalities. Its treatment is multifactorial, including the management of anaemia, iron overload and prevention of osteoporosis. The only treatment specific to CDA-I is subcutaneous interferon alpha (IFNα) 2A. This study presents the first summary of all published cases of CDA-I patients (n = 33) treated with IFNα and categorises their outcome. We also present new unpublished cases (n = 7). Overall, we find that IFNα administration causes a statistically significant mean increase in haemoglobin of 30.7 g/L (p < 0.001). However, we note that previous studies do not assess the impact of IFNα therapy on providing symptomatic benefit to patients with CDA-I, or the weight of side effects on their quality of life. We collaborate directly with patients through the organisation Congenital Anaemia Network to establish patient preferences regarding IFNα treatment. We propose a classification framework for the use of IFNα in CDA-I that includes patient-reported outcome measures in addition to grading response according to changes in Hb levels. We believe that the use of this framework will aid standardisation in measuring response to therapy, improve clinical practice and assist in future research.
2025-10-13 | Congenital Dyserythropoietic Anemia Type II due to Compound Heterozygous SEC23B Mutations Mimicking Thalassemia: A Case of Severe Preventable Morbidity in a Resource-Limited Setting.
IntroductionCongenital Dyserythropoietic Anemia Type II (CDA-II) is a rare autosomal recessive disorder characterized by ineffective erythropoiesis, typically caused by biallelic mutations in the SEC23B gene [1]. This gene encodes a crucial component
cell therapies
2026-08-14 | KLF1 mutation-associated congenital dyserythropoietic anemia type IV: a case report and literature review.
Congenital dyserythropoietic anemia type IV (CDA IV) is a rare inherited erythroid disorder within the broad phenotypic spectrum associated with pathogenic variants in Krüppel-like factor 1 (KLF1), a master transcriptional regulator of erythropoiesis. This study aimed to describe the clinical picture, genetic causes, global distribution, and treatment of CDA IV. We retrospectively reviewed three pediatric patients diagnosed and treated at the Department of Pediatrics, The First Affiliated Hospital of Guangxi Medical University, since December 2014. Demographic, clinical, genetic, laboratory, treatment, transplantation, and follow-up data were collected, including conditioning regimens, graft-versus-host disease (GVHD) prophylaxis, engraftment, complications, and donor chimerism. We also conducted a literature review of CDA IV cases reported worldwide between January 1991 and December 2024. All three children developed symptoms within the first month of life. They had neonatal jaundice and anemia. One of them needed intrauterine transfusion. Gene testing found four KLF1 variants: c.525_526insCGGCGCC, c.1012C > T, c.1012C > A, and c.973G > A. Before hematopoietic stem cell transplantation (HSCT), all three patients needed regular red blood cell transfusions and had iron overload. All three then received HSCT from a parent or sibling. Neutrophils and platelets engrafted in every case. Donor chimerism stayed above 95% during follow-up, and no graft failure happened. No patient had acute or chronic GVHD. Viral reactivation after HSCT was mainly cytomegalovirus (CMV) and Epstein-Barr virus (EBV) infection, and no severe infection was seen. At the last follow-up, all three patients were free of transfusion. Serum ferritin levels went down after HSCT, but liver or heart iron overload did not fully go away in some patients. For carefully chosen children with severe transfusion-dependent KLF1-related red cell disease, allogeneic HSCT may be a feasible curative option. Stable donor chimerism and lasting freedom from transfusion can be achieved. CDA IV has many clinical forms and can be mistaken for thalassemia or Evans syndrome, so early gene testing is very important for correct diagnosis. In areas where thalassemia is common, KLF1 mutation screening should be considered when the cause of microcytic anemia is unclear. Bigger studies with longer follow-up are still needed to better judge the long-term results of HSCT.
2025-06-16 | Haploidentical Hematopoietic Stem Cell Transplantation for the Treatment of Congenital Dyserythropoietic Anemia Combined with Thalassemia: A Report of Two Cases
Congenital dyserythropoietic anemia (CDA) comprises a heterogeneous group of rare hereditary disorders characterized by ineffective erythropoiesis and often presents with clinical features that overlap with thalassemia. Hematopoietic stem cell transplantation (HSCT) remains the only definitive curative intervention for CDA; however, experience with haploidentical HSCT in this population is limited, and the procedure is associated with considerable challenges. We report two pediatric cases of CDA coexisting with thalassemia who underwent haploidentical related donor HSCT using a novel conditioning regimen comprising three alkylating agents. This was combined with graft-versus-host disease prophylaxis utilizing posttransplant cyclophosphamide and anti-thymocyte globulin. Both patients achieved sustained engraftment, transfusion independence, and remained free of severe transplant-related complications. These cases demonstrate the feasibility and therapeutic potential of haploidentical HSCT for patients with CDA, even in the context of concomitant thalassemia.
2024-04-16 | Proteomic analysis reveals a potential role for extracellular vesicles within the erythroblastic island niche
Introduction: Erythroblastic island (EBI) macrophages play an essential role in the production and maturation of the vast numbers of red blood cells (RBCs) that are produced throughout life. Their location within the bone marrow makes it difficult to study the cellular and molecular interactions associated with their action so we have used an in vitro model of the EBI niche using macrophages derived from human induced pluripotent stem cells (hiPSCs). We previously demonstrated that the activation of the transcription factor KLF1 enhanced the activity of hiPSC-derived EBI macrophages. Methods: To elucidate the mechanisms associated with EBI-like activity we carried out a quantitative proteomic analysis and assessed the role of extracellular vesicles using Nanosight Tracking analyses and media filtration. Results and Discussion: Gene ontology analysis showed that many of the proteins upregulated by KLF1 were protein-binding factors, some of which were associated with the cell membrane or extracellular vesicles We demonstrated that filtration of macrophage-conditioned media resulted in a reduction in the supportive effects on erythroid cell viability and maturation implying a role for extracellular vesicles but this was not KLF1 dependent. Pathway analyses of the proteomic data revealed that proteins upregulated by KLF1 were associated with the citric acid cycle, pyruvate metabolism and ATP synthesis indicating that KLF1-activated macrophages had a metabolic profile comparable to a pro-reparative phenotype. This study has generated a proteomic dataset that could provide new insights into the role of macrophages within the EBI niche and has indicated a potential role for extracellular vesicles in the differentiation and maturation of RBCs in vitro . Further research will aid in the production of RBCs in vitro for use in disease modelling and cell therapy.
2022-06-14 | Hematopoietic Cell Transplantation for Congenital Dyserythropoietic Anemia: A Report from the Pediatric Transplant and Cellular Therapy Consortium.
Hematopoietic cell transplantation (HCT) is the sole curative option for congenital dyserythropoietic anemia (CDA), a rare type of hemolytic anemia characterized by anemia, ineffective erythropoiesis, and secondary hemochromatosis. In this retrospective multicenter study, we report the outcomes of children with CDA who underwent HCT at participating Pediatric Transplantation and Cellular Therapy Consortium centers. Clinical information on HCT and associated outcomes was collected retrospectively using a common questionnaire. Data were analyzed using descriptive statistics and appropriate analysis. Eighteen patients with CDA who underwent allogeneic HCT between 2002 and 2020 were identified. The majority of patients (n = 13) had CDA type II, and the remainder had either CDA type I (n = 2) or CDA of unknown type (n = 3). Mutations were identified in 7 patients (39%), including SEC23B in 5, GATA1 in 1, and abnormality of chromosome 20 in 1. Thirteen patients had evidence of iron overload pre-HCT and received chelation therapy for a median duration of 10 months (range, 2 months to 17 years) pre-HCT. The median age at the time of HCT was 5.5 years (range, 0.7 to 26 years). Donors were HLA-matched (sibling, 4; unrelated, 10) and mismatched (haploidentical, 1; unrelated, 3). Graft sources were bone marrow in 15 patients, umbilical cord blood in 2 patients, or both in 1 patient. Conditioning included busulfan-based myeloablative (67%), fludarabine-based reduced-intensity (27%), or nonmyeloablative (6%) regimens. Five patients developed veno-occlusive disease, and 4 had viral reactivation. The cumulative incidence of acute graft-versus-host disease (GVHD) was 33%, and that of chronic GVHD was 22%. Four patients (22%) experienced graft failure; all engrafted following either a second HCT (n = 2) or third HCT (n = 2) but sustained considerable morbidities (3 GVHD, 1 death, 2 viral reactivation). With a median follow-up of 3.2 years (range, 0.6 to 14 years)), the 2-year overall survival, event-free survival (EFS), and GVHD-free EFS were 88% (95% confidence interval [CI], 73% to 100%), 65% (95% CI, 45% to 92%), and 60% (95% CI, 40% to 88%), respectively. Univariate analysis did not identify any patient- or transplantation-related variables impacting outcomes. Our study indicates that HCT can be curative for patients with CDA. Strategies such as aggressive chelation, use of preconditioning therapy, and early HCT in the presence of a suitable donor before comorbidities occur are needed to improve engraftment without increasing the risk for toxicity and mortality.
2020-12-31 | Hematopoietic Stem Cell Transplantation in Congenital Dyserythropetic Anemia Type II: A Case Report and Review of the Literature.
Currently, there is no guideline for the treatment of patients with congenital dyserythropoietic anemia (CDA) type II. One approach is to follow-up patients with transfusions, on the basis of individually determined target hemoglobin levels, and iron chelation according to the thalassemia guidelines. In some transfusion-dependent CDA II patients, splenectomy reduces the number of transfusions; however, the only known curative option for CDA II patients is hematopoietic stem cell transplantation (HSCT). Only a few published case reports of allogeneic HSCT in CDA II patients are available. Here, we review the literature and add our data of a CDA II patient who developed transfusion dependence and was cured with HSCT.
gene therapies
2026-07-15 | Red lines and green lights: Gene therapy for inherited erythroid disorders beyond the haemoglobinopathies.
Gene therapy is revolutionizing treatment paradigms for inherited haematological and immunological conditions. Recent successes, including the United States Food and Drug Administration (FDA) approval of gene therapy products for sickle cell disease and beta-thalassaemia, highlight the translational path of gene therapies for erythroid-specific disorders. In contrast, gene therapy development for other inherited erythroid disorders remains largely preclinical. Here, we examine the emerging landscape of gene therapies for inherited non-haemoglobinopathy erythroid disorders, focusing on the status of gene therapies for Diamond-Blackfan anaemia (DBA), pyruvate kinase deficiency (PKD), X-linked sideroblastic anaemia (XLSA), congenital erythropoietic porphyria (CEP) and congenital dyserythropoietic anaemia (CDA). We discuss the latest cellular engineering approaches being applied to developing therapies for these erythroid disorders and evolving strategies for conditioning and engraftment of modified cells. Despite the rarity of these disorders individually, several convergent biological and translational themes have emerged. Leveraging shared insights across diseases may accelerate clinical translation and broaden the curative potential of gene therapy for inherited erythroid disorders beyond the haemoglobinopathies.
2025-01-01 | Identifying and Validating Novel Regulators of Erythroid Differentiation
Erythrocytes are the most numerous human cell type and are essential to survival, fulfilling the vital role of oxygen delivery throughout the body by means of hemoglobin transport. Situations in which the body does not have enough hemoglobin or erythrocytes result in anemia. Anemia can commonly result from mutations in genes affecting erythroid development (as in the case of congenital dyserythropoietic anemias) or in genes encoding components of hemoglobin (such as sickle cell disease (SCD) or β-thalassemia). One potential treatment strategy for SCD or β-thalassemia is aimed at inducing fetal hemoglobin (HbF), but to date there are few treatment options available to address the unmet needs in anemia. Improved understanding of erythroid development would therefore not only be of significant scientific value but also may help address unmet medical needs. The production of erythrocytes, known as erythropoiesis, is a highly controlled and regulated process. This process is controlled both by soluble hormones that act locally and systemically, and by intrinsic regulators that exist both dependently and independently from external cell signals. While a handful of rigorously examined genes belonging to the groups of extrinsic regulators (ex: EPOR, NR3C1, KIT) and intrinsic regulators (ex: GATA1, KLF1, TAL1) have been identified as key regulators of erythropoiesis, little is known about the necessity of thousands of other genes expressed during erythroid development. In this thesis, I have evaluated the requirement of thousands of genes in erythropoiesis, using a genome-scale CRISPR knock-out screen. Innovations in modeling erythroid development and CRISPR/Cas9 screening have enabled the simultaneous evaluation of all genes in the human genome to identify novel candidate regulators of human erythroid differentiation. Through comparisons of sgRNA abundance in the CRISPR library and erythroid cells before and after differentiation, we have identified genes that are required for the survival of proerythroblasts and genes required for terminal erythroid differentiation. Many of the top genes identified using this screen were well-known regulators of erythropoiesis, validating the utility of this approach. Among highly ranked genes identified in the screen, NHLRC2, which was previously implicated in hemolytic anemia. We suggest that anemia due to NHLRC2 mutation results at least in part from a defect in erythroid differentiation. Another highly ranked novel gene in the screen was VAC14, which was validated for its requirement in erythropoiesis in vitro and in vivo. Thus, data from this CRISPR screen may help classify anemia (as resulting from a defect in differentiation versus other causes) and may ultimately result in the development of therapies addressing the underlying mechanisms that contribute to erythroid disorders.
2024-11-20 | Treatment Options for Congenital Dyserythropoietic Anemias (CDAs): Advances in Bone Marrow Transplantation, Gene Therapy, and Targeted Therapies
Congenital Dyserythropoietic Anaemia (CDA) is a rare genetic disorder that affects the maturation of red blood cells. The disorder is classified into different types, with a prevalence ranging from 1 in 100,000 to 1 in 1,000,000 individuals. Treatment strategies are designed with the primary focus on symptom management, the prevention and treatment of complications, and the underlying disease pathophysiology. The advent of bone marrow transplantation, gene therapy, and targeted therapies has considerably expanded the scope for therapeutic intervention in CDAs. Supportive care, including blood transfusions and iron chelation therapy, has demonstrated efficacy in managing iron overload and improving overall survival rates. The potential of gene therapy, targeted therapies, and hematopoietic growth factors in the treatment of CDA is currently being investigated. Further research and clinical trials are required to develop more effective and personalized therapeutic interventions.
2024-11-05 | Establishing a Patient-Derived Immortalized Erythroid Progenitor Cell Model to Investigate Disease Mechanisms and Lentiviral Gene Therapy Vector in Congenital Dyserythropoietic Anemia Type II
Congenital dyserythropoietic anemias (CDAs) are rare inherited disorders characterized by ineffective erythropoiesis. Type II CDA (CDA II) is the most prevalent, caused by mutations in the SEC23B gene. Clinically, CDA II is manifest by mild to severe anemia, relative reticulocytopenia, jaundice, hepatosplenomegaly, and cholelithiasis. Bone marrow erythroblasts in these patients show erythroid hyperplasia and 10-30% binucleation or occasionally multinucleation. Previous in-vivo models using mice and zebrafish have not accurately replicated the disease phenotypes observed in humans. In this study, we aimed to establish a patient-derived immortalized erythroid progenitor cell (iEPC) model to investigate disease mechanisms. We isolated peripheral blood mononuclear cells (PBMNCs) from two patients with clinical and pathological phenotypes consistent with CDA II, both of whom exhibited SEC23B mutations as identified by next-generation sequencing. One patient, compound heterozygous for mutations NM_006363.4:c.1043A>G and NM_006363.4:c.1898delC, displayed more severe symptoms and was transfusion-dependent, unlike the other patient, who was compound heterozygous for mutations NM_006363.4:c.1589G>A, and NM_006363.4:c.1905+3G>T and did not require transfusions. Using a lentiviral vector, we transduced the PBMNCs with HPV E6/E7 genes and cultured them in erythroid progenitor expansion medium, successfully generating immortalized erythroid progenitors that were maintained for over 90 days. These iEPCs expressed erythroid markers CD71 and CD235a and were predominantly in the proerythroblast or basophilic erythroblast stages. The iEPCs could be differentiated into later stages of erythropoiesis using a cytokine-enriched medium. Despite typical expression kinetics of CD71, CD105, and CD235a during differentiation, the CDA II iEPCs showed reduced enucleation compared to a wild-type iEPC line, indicative of ineffective erythropoiesis. Morphological analysis using Giemsa stain revealed binucleation in 20 to 30% of cells at the orthochromatic stage. Transmission electron microscopy showed a discontinuous double membrane in mature erythroblasts of both CDA lines. Western blot analysis confirmed reduced SEC23B expression in the CDA II lines. RNA sequencing of iEPCs pre- and post-differentiation identified novel pathways involved in disease pathogenesis. After transducing the iEPCs with a lentiviral vector expressing SEC23B, we observed a significant decrease in binucleated cells and an increase in terminally differentiated cells. Our results demonstrate that iEPCs can be successfully generated from patients with rare red cell diseases and that CDA II disease modeling using iEPCs is viable for studying disease mechanisms and evaluating gene therapy vectors.
2023-06-29 | New Cases and Mutations in SEC23B Gene Causing Congenital Dyserythropoietic Anemia Type II.
Congenital dyserythropoietic anemia type II (CDA II) is an inherited autosomal recessive blood disorder which belongs to the wide group of ineffective erythropoiesis conditions. It is characterized by mild to severe normocytic anemia, jaundice, and splenomegaly owing to the hemolytic component. This often leads to liver iron overload and gallstones. CDA II is caused by biallelic mutations in the SEC23B gene. In this study, we report 9 new CDA II cases and identify 16 pathogenic variants, 6 of which are novel. The newly reported variants in SEC23B include three missenses (p.Thr445Arg, p.Tyr579Cys, and p.Arg701His), one frameshift (p.Asp693GlyfsTer2), and two splicing variants (c.1512-2A>G, and the complex intronic variant c.1512-3delinsTT linked to c.1512-16_1512-7delACTCTGGAAT in the same allele). Computational analyses of the missense variants indicated a loss of key residue interactions within the beta sheet and the helical and gelsolin domains, respectively. Analysis of SEC23B protein levels done in patient-derived lymphoblastoid cell lines (LCLs) showed a significant decrease in SEC23B protein expression, in the absence of SEC23A compensation. Reduced SEC23B mRNA expression was only detected in two probands carrying nonsense and frameshift variants; the remaining patients showed either higher gene expression levels or no expression changes at all. The skipping of exons 13 and 14 in the newly reported complex variant c.1512-3delinsTT/c.1512-16_1512-7delACTCTGGAAT results in a shorter protein isoform, as assessed by RT-PCR followed by Sanger sequencing. In this work, we summarize a comprehensive spectrum of SEC23B variants, describe nine new CDA II cases accounting for six previously unreported variants, and discuss innovative therapeutic approaches for CDA II.
other
2025-12-25 | MMS22L is a novel key actor of normal and pathological erythropoiesis.
The emergence of next-generation sequencing techniques has led to the genetic characterization of numerous congenital erythroid disorders, emphasizing crucial pathways in both normal and pathological erythropoiesis. In this study, whole exome sequencing of a single patient with atypical congenital pure red cell aplasia revealed a mutation in the CDAN1 gene, typically associated with congenital dyserythropoietic anemia type 1 (CDAI), together with a previously unreported mutation in the MMS22L gene. Combined mms22l and cdan1 haploinsufficiency results in severe anemia in a zebrafish model. In human erythroid progenitors, loss of MMS22L leads to proliferation and differentiation arrest associated with activation of the p53 pathway and global epigenetic alterations, showing that MMS22L plays an indispensable role in erythropoiesis. Furthermore, MMS22L and CDAN1 are involved in the same protein complex whose nuclear import is mediated by the importin 4 (IPO4) protein, and MMS22L nuclear import is impaired in CDAI patients due to a defective interaction between CDAN1 and IPO4. Overall, through the genetic description of a single case characterized by digenic inheritance, we identified MMS22L as a novel key factor in erythropoiesis and brought new insights into normal erythropoiesis regulation and CDAI pathophysiology.
2024-11-05 | Abatacept Abrogates the Risk of Acute GvHD in Both Matched and Mismatched Transplantation for Haemoglobinopathies and Bone Marrow Failure
Introduction: Allogeneic hematopoietic stem cell transplantation [HCT] is a well-established curative therapy for hemoglobinopathies and bone marrow failure syndromes [BMF]. Advances in conditioning regimens and prophylaxis have reduced the incidence of graft versus host disease [GvHD]. However, GVHD remains the most important factor of morbidity and impacts long-term outcomes. This is particularly important with the advent of HLA-mismatched and haploidentical HCT leading to universal availability of curative treatment for these indications where there is no advantage for a graft versus leukaemia effect. Abatacept is a fusion protein cytotoxic T cell-lymphocyte-4-immunoglobulin [CTLA4-Ig] that induces co-stimulatory blockade of CD80 and CD86 on antigen presenting cells modulating T-cell activation. Abatacept has been shown to result in a reduction of severe GvHD and improved outcomes in the malignant HCT setting [Watkins et al 2021]. Aims: We hypothesised that the addition of abatacept for 6 months to GvHD prophylaxis would result in a reduced rate of acute GVHD in children undergoing HCT for hemoglobinopathies and BMF with improved outcomes. Methods: Between June 2023 and June 2024, 35 consecutive T cell replete HCT received abatacept prophylaxis: 10 mg/kg [day -1, day +5, day +14, day +28, day +60, day +90, day +120, day +150. Results were compared to HCT outcomes from the previous four years. 16 procedures were matched related, 9 matched unrelated, 5 matched unrelated and 5 haploidentical HCT. 15 children had sickle cell disease, 8 transfusion dependent thalassemia, 4 for Diamond-Blackfan anemia, 2 Fanconi anemia, 2 congenital dyserythropoietic anemia and 4 for severe aplastic anemia. The outcomes were compared to a historical control group of 66 consecutive HCT between January 2020 and May 2023 at the same institution using the same conditioning regimens but without abatacept prophylaxis. The median age was the 11 years of age in both groups (abatacept group range 2-18 years and control group 2-19 years). The source of stem cells consisted of 31 bone marrow and 4 PBSC in the abatacept group whereas the control group had no PBSC use. The median follow-up was 6.4 months (0.95 - 12.9) for the abatacept group and 15.9 months for the control group (1.5 - 42.5). Estimates for the probability were calculated using the Kaplan-Meier statistical approach. Results: All patients in the abatacept group engrafted and are alive whereas there were 2 cases of graft failure (3%) and 3 deaths (4.5%) in the control group. Median neutrophil engraftment was 16.5 days (11-28) in the abatacept group and 13 days (9-29). The probability of acute GVHD grade II-IV was significantly lower in the abatacept group: 6.6% (2 cases) versus 39.7% in the control group (26 cases), p <0.001. There were no cases of acute GvHD grade III-IV in the abatacept group whereas there were 11 (16.8%) of which one was grade 4 in the control group, P 0.016. This was associated with a median cessation of immunosuppression of 180 days (108-295) in the abatacept group (n = 13) versus 216 days (106-523) in the control group. The OS and EFS at 1 year was 100% for the abatacept group whereas the 96.8% and 93.6% respectively for the control group. Conclusion: Abatacept reduces the risk of grade II-IV acute GVHD in both matched and mismatched pediatric HCT for non-malignant disorders including hemoglobinopathies and bone marrow failure syndromes. Further, abatacept resulted in a reduction in the duration of immunosuppression. It is particularly effective in abrogating the risk of severe acute GvHD. It was well tolerated with no associated toxicity with its use. References: WatkinB, Qayed M, McCracken C, et al. Phase II trial of costimulation blockade with abatacept for prevention of acute GVHD. J Clin Oncol. 2021. ;39(17):1865-1877.
2021-09-15 | Majeed Syndrome: A Review of the Clinical, Genetic and Immunologic Features.
Majeed syndrome is a multi-system inflammatory disorder affecting humans that presents with chronic multifocal osteomyelitis, congenital dyserythropoietic anemia, with or without a neutrophilic dermatosis. The disease is an autosomal recessive disorder caused by mutations in LPIN2, the gene encoding the phosphatidic acid phosphatase LIPIN2. It is exceedingly rare. There are only 24 individuals from 10 families with genetically confirmed Majeed syndrome reported in the literature. The early descriptions of Majeed syndrome reported severely affected children with recurrent fevers, severe multifocal osteomyelitis, failure to thrive, and marked elevations of blood inflammatory markers. As more affected families have been identified, it has become clear that there is significant phenotypic variability. Data supports that disruption of the phosphatidic acid phosphatase activity in LIPIN2 results in immune dysregulation due to aberrant activation of the NLRP3 inflammasome and overproduction of proinflammatory cytokines including IL-1β, however, these findings did not explain the bone phenotype. Recent studies demonstrate that LPIN2 deficiency drives pro-inflammatory M2-macrophages and enhances osteoclastogenesis which suggest a critical role of lipin-2 in controlling homeostasis at the growth plate in an inflammasome-independent manner. While there are no approved medications for Majeed syndrome, pharmacologic blockade of the interleukin-1 pathway has been associated with rapid clinical improvement.
2015-02-24 | New insights into iron regulation and erythropoiesis
Purpose of review Iron homeostasis and erythropoiesis regulate each other to ensure optimal delivery of oxygen and iron to cells and tissues. Defining the mechanisms of this crosstalk is important for understanding the pathogenesis of common conditions associated with disordered iron metabolism and erythropoiesis. Recent findings Stress erythropoiesis causes suppression of hepcidin to increase iron availability for hemoglobin synthesis. The erythroid hormone erythroferrone (ERFE) was identified as the mediator of this process. ERFE and additional candidates (TWSG1 and GDF15) may also mediate hepcidin suppression in ineffective erythropoiesis. Several mechanisms by which iron regulates erythropoiesis were also recently identified. Iron deficiency suppresses erythropoietin production via the IRP1–HIF2α axis to prevent excessive iron usage by erythropoiesis during systemic iron restriction. Iron restriction also directly impairs erythroid maturation by inhibiting aconitase, and this can be reversed by the administration of the aconitase product isocitrate. Another novel target is GDF11, which is thought to autoinhibit erythroid maturation. GDF11 traps show promising pharmacologic activity in models of both ineffective erythropoiesis and iron-restricted anemia. Summary This review summarizes exciting advances in understanding the mechanisms of iron and erythropoietic regulation, and development of novel therapeutic tools for disorders resulting from dysregulation of iron metabolism or erythropoiesis.
2012-09-26 | Naturally Occurring Anti-Band 3 Antibodies in Clearance of Senescent and Oxidatively Stressed Human Red Blood Cells
Naturally occurring anti-band 3 antibodies (anti-band 3 NAbs) are directed against the 55-kDa chymotryptic fragment of the anion transport protein (band 3) of red blood cells (RBCs). They bind to senescent and oxidatively stressed RBCs and induce their selective clearance. These IgG NAbs exist at low concentrations, and have a weak affinity that prevents them from actively recruiting second binding sites. Cellular senescence or oxidative damage induces a cascade of biochemical events that results in the detachment of band 3 from the cytoskeleton and in clustering of band 3 protein by bound hemichromes and Syk kinase. Clustered band 3 proteins allow bivalent binding of anti-band 3 NAbs. Bivalently bound anti-band 3 NAbs have the unique capacity to stimulate C3b deposition by preferentially generating C3b2-IgG complexes, which act as potent C3 convertase precursors of the alternative complement pathway. Antibody binding not only to clustered, but also to oligomerized band 3 protein further increases if the human plasma also contains induced anti-lactoferrin antibodies. These bind to the polylactosaminyl oligosaccharide, a carbohydrate that exists in lactoferrin and in the 38-kDa fragment of band 3 protein. Anti-lactoferrin antibodies are found primarily in plasma of patients with autoimmune diseases and who have anti-neutrophil cytoplasmic antibodies (ANCA).Natürlicherweise vorkommende Anti-Bande-3-Antikörper (Anti-Bande-3-NAbs) sind gegen das chymotrypti-sche 55-kDa-Fragment des Anionenaustauschproteins der roten Blutkörperchen (RBCs) (Bande 3) gerichtet, binden an alte und oxidativ geschädigte RBCs und induzieren deren selektive Phagozytose. Diese NAbs sind IgG-Immunglobuline und haben eine schwache Affinität, welche sie daran hindert, aktiv Zweitbindungsstellen zu rekrutieren. Zelluläre Alterung oder oxidative Schädigungen induzieren eine Kaskade von biochemischen Vorgängen, die in der Ablösung der Bande-3-Proteine vom Zytoskelett resultieren und die Verklumpung von Bande 3 in der Membran durch die Bindung von Hemichromen und Syk-Kinase begünstigen. Verklumpte Bande-3-Proteine erlauben eine bivalente Bindung der Anti-Bande-3-NAbs. Bivalent gebundene Anti-Bande-3-NAbs haben die Fähigkeit, die C3b-Deposition zu stimulieren indem sie präferentiell C3b2-IgG bilden, die als potente Vorläufer von alternativen C3-Konvertasen wirken. Die Antikörper-Bindung nicht nur an verklumpte, sondern bereits an oligomerisierte Bande-3-Proteine steigt weiter an, wenn humanes Plasma auch induzierte Anti-Laktoferrin-Antikörper enthält, die an das Polylactosylaminyl-Kohlehydrat binden, das in Laktoferrin vorkommt aber auch im 38-kDa-Fragment des Bande-3-Proteins. Anti-Laktoferrin-Antikörper treten bevorzugt im Plasma von Patienten mit Autoimmunkrankheiten auf, insbesondere solchen, die sich durch anti-neutrophile zytoplasmatische Antikörper (ANCA) auszeichnen.
small molecules
2026-07-28 | Case Report: HCV-triggered porphyria cutanea tarda in a patient with SEC23B-mutated congenital dyserythropoietic anemia type II.
Porphyria cutanea tarda (PCT) is a hepatic porphyria often triggered by hepatitis C virus (HCV) infection, iron overload, or environmental exposure. Congenital dyserythropoietic anemia type II (CDA II) caused by SEC23B mutations leads to ineffective erythropoiesis and secondary iron accumulation. We report a 34-year-old man with genetically confirmed SEC23B-mutated CDA II who developed photosensitive bullae associated with chronic HCV genotype 1b infection, hyperbilirubinemia, and severe iron overload. Urinary porphyrins were positive, and skin biopsy showed subepidermal bullae with PAS-positive deposits, supporting the diagnosis of PCT. After unsuccessful therapy with hydroxychloroquine, treatment with sofosbuvir/velpatasvir achieved sustained virologic response, resolution of skin lesions, and marked ferritin reduction. This case illustrates that viral and metabolic stressors can trigger PCT in CDA II patients with possible hepatic involvement, underscoring the importance of recognizing combined genetic and infectious factors in rare hematologic disorders.
2026-05-25 | KIF23 in disease pathogenesis and its therapeutic and diagnostic potential.
Kinesin family member 23 (KIF23) is a microtubule-dependent motor protein essential for cytokinesis, organelle transport, and signaling pathway regulation. Its dysregulation contributes to both tumorigenesis and non-malignant disorders; however, a comprehensive review integrating recent mechanistic and translational insights is currently lacking. A literature search across PubMed, Web of Science, Embase, and public databases (such as TCGA), using keywords including "KIF23," "MKLP1," and "cytokinesis" was performed. Published bioinformatic findings, including pan cancer screening and machine learning analyses, linking KIF23 to disease pathogenesis were summarized. KIF23 is frequently upregulated in various cancers, such as colorectal, gastric, hepatocellular and breast cancer, where it activates key oncogenic pathways including Wnt/β-catenin, PI3K-Akt and NF-κB. It remodels the tumor immune microenvironment and correlates with poor prognosis. In contrast, loss-of-function mutations in KIF23 underlie several non-neoplastic diseases, such as congenital dyserythropoietic anemia type III and primary microcephaly, by causing cytokinesis failure and developmental defects. KIF23 expression is regulated through multilayered networks involving transcriptional, epigenetic and competing endogenous RNA (ceRNA) mechanisms. Preclinical studies underscore its potential as a diagnostic biomarker and a promising therapeutic target. KIF23 plays a context-dependent, dual role in disease pathogenesis and represents a compelling target for precision medicine. Future research should focus on deciphering the functional heterogeneity of its splice variants, developing tumor-selective inhibitors and validating integrated biomarker panels to advance clinical translation.
2026-01-12 | Use of Post-Transplant Cyclophosphamide in Matched Related and Unrelated Donor Hematopoietic Stem Cell Transplant for Benign Hematological Disorders.
Introduction of Post-Transplant Cyclophosphamide (PTCy) based immunosuppression in Haploidentical Hematopoietic Stem Cell Transplants (HSCT) has shown to reduce the incidence of Graft vs. Host Disease (GVHD). However, data on its use in HLA matched settings is lacking. We describe our experience using PTCY in pediatric patients undergoing matched donor HSCT. We retrospectively analysed data of 16 patients who underwent HLA-matched HSCT using PTCy from March 2022-July 2024 at our institute. Sixteen patients of median age-6 years (Range:1-17 years) were analysed. Indications of transplant were Thalassemia in 10, severe aplastic anemia in 5 and Congenital dyserythropoietic anemia in 1. Conditioning regimes used were Rabbit ATG-Thio-Flu-Cy-2 Gy TBI in 8 and Rabbit ATG-Thio-Treo-Flu-2 Gy TBI in 3 which was preceded by two cycles of pre-transplant immunosuppression (PTIS); Rabbit ATG-Flu-Cy-4 Gy TBI in 5 patients of aplastic anemia. PTCy, Mycophenolate mofetil and cyclosporine were used as GVHD prophylaxis. One patient had primary and another had CMV induced secondary graft failure. Three patients had grade I-II acute GVHD at median 32days post HSCT (Range: 28-140days). None of the patients had chronic GVHD. CMV reactivation occurred in 8 patients at a median + 21 days (Range: 14-35 days). Median follow up duration post HSCT was 473days (Range:85-808 days). 1 year- Event-free and 1 year-overall survival rates were 81.25% and 93.7% respectively. PTCy-based approach appears to be promising in matched related and unrelated donor transplants for benign hematological disorders.
2025-05-24 | Angioid streaks and optic disc drusen in a patient with congenital dyserythropoietic anaemia.
A man in his 60s with dry eye symptoms was noted to have angioid streaks under the peripapillary retina. Congenital dyserythropoietic anaemia was the major health issue throughout his life, requiring venesection for iron overload, but no transfusions for many years. Close inspection of the eyes with optical coherence tomography also detected small subclinical optic disc drusen, which have not been reported in association with congenital dyserythropoietic anaemia. Together, optic disc drusen and angioid streaks represent an ectopic calcification phenotype in the eye and can be seen in the more common inherited condition of pseudoxanthoma elasticum or other inherited haemolytic anaemias such as sickle cell or thalassaemia. These associations highlight the role of pyrophosphate as a physiological inhibitor of calcification, and deficiencies of serum pyrophosphate lead to excessive and ectopic calcification. This raises intriguing hypotheses for the treatment of optic disc drusen, angioid streaks and other conditions of ectopic calcification.
2024-08-03 | Use Of Post Transplant Cyclophosphamide In Matched Related And Unrelated Donor Hematopoietic Stem Cell Transplant For Benign Hematological Disorders
Background: Introduction of Post-Transplant Cyclophosphamide (PTCy) based immunosuppression in Haploidentical Hematopoietic Stem Cell Transplants (HSCT) has shown to reduce the incidence of Graft vs Host Disease (GVHD). However, data on its use in HLA matched settings is lacking. Here we describe our experience using PTCY in pediatric patients undergoing HSCT for the same. Methods: We retrospectively analysed data of 16 pediatric patients who underwent HLA matched HSCT using PTCy from March 2022 to November 2023 at our institute. Results: Sixteen patients of median age-6 years (Range: 1 to 17 years) were analysed. Male: female ratio was 3.3:1. Indications of transplant were Thalassemia major in 10, severe aplastic anemia in 5 and Congenital dyserythropoietic anemia type II in 1. Conditioning regimes used were Rabbit ATG-Thio-Flu-Cy-2Gy TBI in 8 and Rabbit ATG-Thio-Treo-Flu-2Gy TBI in 3 which was preceded by two cycles of pre-transplant immunosuppression (PTIS); Rabbit ATG-Flu-Cy-4Gy TBI in 5 patients. Median CD34 dose was 5.1 million/kg (Range: 4.7 to 5.6 million/kg). PTCy (50 mg/kg on d+3, +4), Mycophenolate mofetil and cyclosporine were used as GVHD prophylaxis. Fifteen patients had neutrophil enlargement at median 16 days (Range:11- 21 days). One patient had primary and one had secondary graft failure. Cytomegalovirus reactivation was seen in 8 patients. Of the 14 evaluable patients, 3 patients had grade I-II acute GVHD at median 32 days post HSCT (Range: 28-140days). None of the patients had chronic GVHD. Median follow up duration post HSCT was 473 days (Range: 85-808 days). Event free and overall survival rates were 81.25% and 93.7% respectively. Conclusion: PTCy based approach appears to be promising in matched related and unrelated donor transplants for benign hematological disorders.
proteins
2026-08-04 | Identification of a Novel Compound Heterozygous SEC23B in a Chinese Child with Congenital Dyserythropoietic Anemia Type II.
Congenital dyserythropoietic anemia type II (CDA II) is a rare hyporegenerative inherited anemia, resulting from a mutation in SEC23B. In the present case, our patient exhibited moderate anemia, jaundice, hepatosplenomegaly, tea-colored urine, hyperbilirubinemia, and iron overload. Whole exome sequencing revealed that the patient carried a compound heterozygous genotype in SEC23B consisting of a previously unreported missense variant c.181T > C (p.C61R) and a known pathogenic variant c.1832G > A (p.R611Q). Bone marrow aspirate demonstrated erythroid hyperplasia with abnormal erythroblast morphology. Bioinformatic analysis predicted the protein structures, indicating that p.C61R and p.R611Q mutations induce structural changes in their surrounding regions. SEC23B mRNA and protein levels in peripheral blood mononuclear cells (PBMCs) were significantly reduced compared with those in normal control cells, supporting their pathogenicity. Accordingly, a diagnosis of CDA II was considered. In this study, we identified a compound heterozygous SEC23B genotype in the patient and demonstrated that missense mutations of p.C61R and p.R611Q resulted in reduced levels of SEC23B mRNA and protein, suggesting the association of this genotype with CDA II.
2026-02-09 | Additive effect of multiple genetic variants in SEC23B and PIEZO1 on iron metabolism dyshomeostasis in hereditary anemias.
Hereditary anemias encompass a genetically heterogeneous spectrum of disorders, often involving multi-locus inheritance, which can complicate clinical management and worsen disease severity. This study investigates the impact of the co-inheritance of SEC23B loss-of-function pathogenic variants, which lead to congenital dyserythropoietic anemia type II (CDA II), and PIEZO1 gain-of-function pathogenic variants, associated with dehydrated hereditary stomatocytosis type I (DHS1), on hematological parameters and iron metabolism. Among 583 patients with suspected hereditary anemia, 13 were found to carry both SEC23B and PIEZO1 variants, leading to a dual diagnosis of CDA II and DHS1. Compared to those with isolated CDA II, these patients exhibited a significantly higher absolute reticulocyte count and bone marrow responsiveness index, alongside an increased prevalence of elevated ferritin levels. Functional studies in Hep3B human hepatoma cells confirmed that SEC23B knockdown combined with PIEZO1 gain-of-function led to marked ferritin accumulation and reduced hepcidin expression, driven by altered BMP/SMAD signaling and ERK1/2 MAPK pathway. These findings demonstrate how multi-locus inheritance can modify disease severity, particularly by exacerbating iron overload. Our results underscore the clinical relevance of comprehensive genetic testing for enhanced risk stratification and personalized management of hereditary anemias.
2026-01-29 | Anemia-associated mutations disrupt the CDIN1-Codanin1 complex in inherited congenital dyserythropoietic anemia I (CDA-I) disease.
Congenital dyserythropoietic anemia type I (CDA-I) is a rare hereditary disease marked by ineffective erythropoiesis, a characteristic spongy heterochromatin structure in erythroblasts, and mutations in the genes CDAN1 and CDIN1, which encode the proteins Codanin1 and CDIN1. Codanin1 regulates histone shuttling via the chaperone ASF1, yet the role of CDIN1 in CDA-I pathology remains unclear. Notably, CDIN1 is known to interact directly with the C-terminus of Codanin1. Although mutations in both genes are critical to the disease phenotype, their molecular-level effects have not been fully elucidated. Here, we present a comprehensive structural and functional analysis of the CDIN1-Codanin1 C-terminus complex. Using complementary biophysical techniques, we show that CDIN1 and Codanin1 C-terminus form a high-affinity heterodimeric complex with equimolar stoichiometry. We further delineate the essential interacting regions of CDIN1 and Codanin1. We demonstrate that CDA-I-associated mutations in either protein disrupt the CDIN1-Codanin1 interaction, suggesting a potential molecular mechanism underlying the disease.
2026-01-28 | Using Patient Feedback to Improve Treatment Outcomes for Patients with Congenital Dyserythropoietic Anaemia Type I Receiving Interferon Therapy.
Congenital dyserythropoietic anaemia type-I (CDA-I) is a rare autosomal recessive disease characterised by ineffective erythropoiesis, haemolysis and non-haematological developmental abnormalities. Its treatment is multifactorial, including the management of anaemia, iron overload and prevention of osteoporosis. The only treatment specific to CDA-I is subcutaneous interferon alpha (IFNα) 2A. This study presents the first summary of all published cases of CDA-I patients (n = 33) treated with IFNα and categorises their outcome. We also present new unpublished cases (n = 7). Overall, we find that IFNα administration causes a statistically significant mean increase in haemoglobin of 30.7 g/L (p < 0.001). However, we note that previous studies do not assess the impact of IFNα therapy on providing symptomatic benefit to patients with CDA-I, or the weight of side effects on their quality of life. We collaborate directly with patients through the organisation Congenital Anaemia Network to establish patient preferences regarding IFNα treatment. We propose a classification framework for the use of IFNα in CDA-I that includes patient-reported outcome measures in addition to grading response according to changes in Hb levels. We believe that the use of this framework will aid standardisation in measuring response to therapy, improve clinical practice and assist in future research.
2025-10-13 | Congenital Dyserythropoietic Anemia Type II due to Compound Heterozygous SEC23B Mutations Mimicking Thalassemia: A Case of Severe Preventable Morbidity in a Resource-Limited Setting.
IntroductionCongenital Dyserythropoietic Anemia Type II (CDA-II) is a rare autosomal recessive disorder characterized by ineffective erythropoiesis, typically caused by biallelic mutations in the SEC23B gene [1]. This gene encodes a crucial component
cell therapies
2026-08-14 | KLF1 mutation-associated congenital dyserythropoietic anemia type IV: a case report and literature review.
Congenital dyserythropoietic anemia type IV (CDA IV) is a rare inherited erythroid disorder within the broad phenotypic spectrum associated with pathogenic variants in Krüppel-like factor 1 (KLF1), a master transcriptional regulator of erythropoiesis. This study aimed to describe the clinical picture, genetic causes, global distribution, and treatment of CDA IV. We retrospectively reviewed three pediatric patients diagnosed and treated at the Department of Pediatrics, The First Affiliated Hospital of Guangxi Medical University, since December 2014. Demographic, clinical, genetic, laboratory, treatment, transplantation, and follow-up data were collected, including conditioning regimens, graft-versus-host disease (GVHD) prophylaxis, engraftment, complications, and donor chimerism. We also conducted a literature review of CDA IV cases reported worldwide between January 1991 and December 2024. All three children developed symptoms within the first month of life. They had neonatal jaundice and anemia. One of them needed intrauterine transfusion. Gene testing found four KLF1 variants: c.525_526insCGGCGCC, c.1012C > T, c.1012C > A, and c.973G > A. Before hematopoietic stem cell transplantation (HSCT), all three patients needed regular red blood cell transfusions and had iron overload. All three then received HSCT from a parent or sibling. Neutrophils and platelets engrafted in every case. Donor chimerism stayed above 95% during follow-up, and no graft failure happened. No patient had acute or chronic GVHD. Viral reactivation after HSCT was mainly cytomegalovirus (CMV) and Epstein-Barr virus (EBV) infection, and no severe infection was seen. At the last follow-up, all three patients were free of transfusion. Serum ferritin levels went down after HSCT, but liver or heart iron overload did not fully go away in some patients. For carefully chosen children with severe transfusion-dependent KLF1-related red cell disease, allogeneic HSCT may be a feasible curative option. Stable donor chimerism and lasting freedom from transfusion can be achieved. CDA IV has many clinical forms and can be mistaken for thalassemia or Evans syndrome, so early gene testing is very important for correct diagnosis. In areas where thalassemia is common, KLF1 mutation screening should be considered when the cause of microcytic anemia is unclear. Bigger studies with longer follow-up are still needed to better judge the long-term results of HSCT.
2025-06-16 | Haploidentical Hematopoietic Stem Cell Transplantation for the Treatment of Congenital Dyserythropoietic Anemia Combined with Thalassemia: A Report of Two Cases
Congenital dyserythropoietic anemia (CDA) comprises a heterogeneous group of rare hereditary disorders characterized by ineffective erythropoiesis and often presents with clinical features that overlap with thalassemia. Hematopoietic stem cell transplantation (HSCT) remains the only definitive curative intervention for CDA; however, experience with haploidentical HSCT in this population is limited, and the procedure is associated with considerable challenges. We report two pediatric cases of CDA coexisting with thalassemia who underwent haploidentical related donor HSCT using a novel conditioning regimen comprising three alkylating agents. This was combined with graft-versus-host disease prophylaxis utilizing posttransplant cyclophosphamide and anti-thymocyte globulin. Both patients achieved sustained engraftment, transfusion independence, and remained free of severe transplant-related complications. These cases demonstrate the feasibility and therapeutic potential of haploidentical HSCT for patients with CDA, even in the context of concomitant thalassemia.
2024-04-16 | Proteomic analysis reveals a potential role for extracellular vesicles within the erythroblastic island niche
Introduction: Erythroblastic island (EBI) macrophages play an essential role in the production and maturation of the vast numbers of red blood cells (RBCs) that are produced throughout life. Their location within the bone marrow makes it difficult to study the cellular and molecular interactions associated with their action so we have used an in vitro model of the EBI niche using macrophages derived from human induced pluripotent stem cells (hiPSCs). We previously demonstrated that the activation of the transcription factor KLF1 enhanced the activity of hiPSC-derived EBI macrophages. Methods: To elucidate the mechanisms associated with EBI-like activity we carried out a quantitative proteomic analysis and assessed the role of extracellular vesicles using Nanosight Tracking analyses and media filtration. Results and Discussion: Gene ontology analysis showed that many of the proteins upregulated by KLF1 were protein-binding factors, some of which were associated with the cell membrane or extracellular vesicles We demonstrated that filtration of macrophage-conditioned media resulted in a reduction in the supportive effects on erythroid cell viability and maturation implying a role for extracellular vesicles but this was not KLF1 dependent. Pathway analyses of the proteomic data revealed that proteins upregulated by KLF1 were associated with the citric acid cycle, pyruvate metabolism and ATP synthesis indicating that KLF1-activated macrophages had a metabolic profile comparable to a pro-reparative phenotype. This study has generated a proteomic dataset that could provide new insights into the role of macrophages within the EBI niche and has indicated a potential role for extracellular vesicles in the differentiation and maturation of RBCs in vitro . Further research will aid in the production of RBCs in vitro for use in disease modelling and cell therapy.
2022-06-14 | Hematopoietic Cell Transplantation for Congenital Dyserythropoietic Anemia: A Report from the Pediatric Transplant and Cellular Therapy Consortium.
Hematopoietic cell transplantation (HCT) is the sole curative option for congenital dyserythropoietic anemia (CDA), a rare type of hemolytic anemia characterized by anemia, ineffective erythropoiesis, and secondary hemochromatosis. In this retrospective multicenter study, we report the outcomes of children with CDA who underwent HCT at participating Pediatric Transplantation and Cellular Therapy Consortium centers. Clinical information on HCT and associated outcomes was collected retrospectively using a common questionnaire. Data were analyzed using descriptive statistics and appropriate analysis. Eighteen patients with CDA who underwent allogeneic HCT between 2002 and 2020 were identified. The majority of patients (n = 13) had CDA type II, and the remainder had either CDA type I (n = 2) or CDA of unknown type (n = 3). Mutations were identified in 7 patients (39%), including SEC23B in 5, GATA1 in 1, and abnormality of chromosome 20 in 1. Thirteen patients had evidence of iron overload pre-HCT and received chelation therapy for a median duration of 10 months (range, 2 months to 17 years) pre-HCT. The median age at the time of HCT was 5.5 years (range, 0.7 to 26 years). Donors were HLA-matched (sibling, 4; unrelated, 10) and mismatched (haploidentical, 1; unrelated, 3). Graft sources were bone marrow in 15 patients, umbilical cord blood in 2 patients, or both in 1 patient. Conditioning included busulfan-based myeloablative (67%), fludarabine-based reduced-intensity (27%), or nonmyeloablative (6%) regimens. Five patients developed veno-occlusive disease, and 4 had viral reactivation. The cumulative incidence of acute graft-versus-host disease (GVHD) was 33%, and that of chronic GVHD was 22%. Four patients (22%) experienced graft failure; all engrafted following either a second HCT (n = 2) or third HCT (n = 2) but sustained considerable morbidities (3 GVHD, 1 death, 2 viral reactivation). With a median follow-up of 3.2 years (range, 0.6 to 14 years)), the 2-year overall survival, event-free survival (EFS), and GVHD-free EFS were 88% (95% confidence interval [CI], 73% to 100%), 65% (95% CI, 45% to 92%), and 60% (95% CI, 40% to 88%), respectively. Univariate analysis did not identify any patient- or transplantation-related variables impacting outcomes. Our study indicates that HCT can be curative for patients with CDA. Strategies such as aggressive chelation, use of preconditioning therapy, and early HCT in the presence of a suitable donor before comorbidities occur are needed to improve engraftment without increasing the risk for toxicity and mortality.
2020-12-31 | Hematopoietic Stem Cell Transplantation in Congenital Dyserythropetic Anemia Type II: A Case Report and Review of the Literature.
Currently, there is no guideline for the treatment of patients with congenital dyserythropoietic anemia (CDA) type II. One approach is to follow-up patients with transfusions, on the basis of individually determined target hemoglobin levels, and iron chelation according to the thalassemia guidelines. In some transfusion-dependent CDA II patients, splenectomy reduces the number of transfusions; however, the only known curative option for CDA II patients is hematopoietic stem cell transplantation (HSCT). Only a few published case reports of allogeneic HSCT in CDA II patients are available. Here, we review the literature and add our data of a CDA II patient who developed transfusion dependence and was cured with HSCT.
gene therapies
2026-07-15 | Red lines and green lights: Gene therapy for inherited erythroid disorders beyond the haemoglobinopathies.
Gene therapy is revolutionizing treatment paradigms for inherited haematological and immunological conditions. Recent successes, including the United States Food and Drug Administration (FDA) approval of gene therapy products for sickle cell disease and beta-thalassaemia, highlight the translational path of gene therapies for erythroid-specific disorders. In contrast, gene therapy development for other inherited erythroid disorders remains largely preclinical. Here, we examine the emerging landscape of gene therapies for inherited non-haemoglobinopathy erythroid disorders, focusing on the status of gene therapies for Diamond-Blackfan anaemia (DBA), pyruvate kinase deficiency (PKD), X-linked sideroblastic anaemia (XLSA), congenital erythropoietic porphyria (CEP) and congenital dyserythropoietic anaemia (CDA). We discuss the latest cellular engineering approaches being applied to developing therapies for these erythroid disorders and evolving strategies for conditioning and engraftment of modified cells. Despite the rarity of these disorders individually, several convergent biological and translational themes have emerged. Leveraging shared insights across diseases may accelerate clinical translation and broaden the curative potential of gene therapy for inherited erythroid disorders beyond the haemoglobinopathies.
2025-01-01 | Identifying and Validating Novel Regulators of Erythroid Differentiation
Erythrocytes are the most numerous human cell type and are essential to survival, fulfilling the vital role of oxygen delivery throughout the body by means of hemoglobin transport. Situations in which the body does not have enough hemoglobin or erythrocytes result in anemia. Anemia can commonly result from mutations in genes affecting erythroid development (as in the case of congenital dyserythropoietic anemias) or in genes encoding components of hemoglobin (such as sickle cell disease (SCD) or β-thalassemia). One potential treatment strategy for SCD or β-thalassemia is aimed at inducing fetal hemoglobin (HbF), but to date there are few treatment options available to address the unmet needs in anemia. Improved understanding of erythroid development would therefore not only be of significant scientific value but also may help address unmet medical needs. The production of erythrocytes, known as erythropoiesis, is a highly controlled and regulated process. This process is controlled both by soluble hormones that act locally and systemically, and by intrinsic regulators that exist both dependently and independently from external cell signals. While a handful of rigorously examined genes belonging to the groups of extrinsic regulators (ex: EPOR, NR3C1, KIT) and intrinsic regulators (ex: GATA1, KLF1, TAL1) have been identified as key regulators of erythropoiesis, little is known about the necessity of thousands of other genes expressed during erythroid development. In this thesis, I have evaluated the requirement of thousands of genes in erythropoiesis, using a genome-scale CRISPR knock-out screen. Innovations in modeling erythroid development and CRISPR/Cas9 screening have enabled the simultaneous evaluation of all genes in the human genome to identify novel candidate regulators of human erythroid differentiation. Through comparisons of sgRNA abundance in the CRISPR library and erythroid cells before and after differentiation, we have identified genes that are required for the survival of proerythroblasts and genes required for terminal erythroid differentiation. Many of the top genes identified using this screen were well-known regulators of erythropoiesis, validating the utility of this approach. Among highly ranked genes identified in the screen, NHLRC2, which was previously implicated in hemolytic anemia. We suggest that anemia due to NHLRC2 mutation results at least in part from a defect in erythroid differentiation. Another highly ranked novel gene in the screen was VAC14, which was validated for its requirement in erythropoiesis in vitro and in vivo. Thus, data from this CRISPR screen may help classify anemia (as resulting from a defect in differentiation versus other causes) and may ultimately result in the development of therapies addressing the underlying mechanisms that contribute to erythroid disorders.
2024-11-20 | Treatment Options for Congenital Dyserythropoietic Anemias (CDAs): Advances in Bone Marrow Transplantation, Gene Therapy, and Targeted Therapies
Congenital Dyserythropoietic Anaemia (CDA) is a rare genetic disorder that affects the maturation of red blood cells. The disorder is classified into different types, with a prevalence ranging from 1 in 100,000 to 1 in 1,000,000 individuals. Treatment strategies are designed with the primary focus on symptom management, the prevention and treatment of complications, and the underlying disease pathophysiology. The advent of bone marrow transplantation, gene therapy, and targeted therapies has considerably expanded the scope for therapeutic intervention in CDAs. Supportive care, including blood transfusions and iron chelation therapy, has demonstrated efficacy in managing iron overload and improving overall survival rates. The potential of gene therapy, targeted therapies, and hematopoietic growth factors in the treatment of CDA is currently being investigated. Further research and clinical trials are required to develop more effective and personalized therapeutic interventions.
2024-11-05 | Establishing a Patient-Derived Immortalized Erythroid Progenitor Cell Model to Investigate Disease Mechanisms and Lentiviral Gene Therapy Vector in Congenital Dyserythropoietic Anemia Type II
Congenital dyserythropoietic anemias (CDAs) are rare inherited disorders characterized by ineffective erythropoiesis. Type II CDA (CDA II) is the most prevalent, caused by mutations in the SEC23B gene. Clinically, CDA II is manifest by mild to severe anemia, relative reticulocytopenia, jaundice, hepatosplenomegaly, and cholelithiasis. Bone marrow erythroblasts in these patients show erythroid hyperplasia and 10-30% binucleation or occasionally multinucleation. Previous in-vivo models using mice and zebrafish have not accurately replicated the disease phenotypes observed in humans. In this study, we aimed to establish a patient-derived immortalized erythroid progenitor cell (iEPC) model to investigate disease mechanisms. We isolated peripheral blood mononuclear cells (PBMNCs) from two patients with clinical and pathological phenotypes consistent with CDA II, both of whom exhibited SEC23B mutations as identified by next-generation sequencing. One patient, compound heterozygous for mutations NM_006363.4:c.1043A>G and NM_006363.4:c.1898delC, displayed more severe symptoms and was transfusion-dependent, unlike the other patient, who was compound heterozygous for mutations NM_006363.4:c.1589G>A, and NM_006363.4:c.1905+3G>T and did not require transfusions. Using a lentiviral vector, we transduced the PBMNCs with HPV E6/E7 genes and cultured them in erythroid progenitor expansion medium, successfully generating immortalized erythroid progenitors that were maintained for over 90 days. These iEPCs expressed erythroid markers CD71 and CD235a and were predominantly in the proerythroblast or basophilic erythroblast stages. The iEPCs could be differentiated into later stages of erythropoiesis using a cytokine-enriched medium. Despite typical expression kinetics of CD71, CD105, and CD235a during differentiation, the CDA II iEPCs showed reduced enucleation compared to a wild-type iEPC line, indicative of ineffective erythropoiesis. Morphological analysis using Giemsa stain revealed binucleation in 20 to 30% of cells at the orthochromatic stage. Transmission electron microscopy showed a discontinuous double membrane in mature erythroblasts of both CDA lines. Western blot analysis confirmed reduced SEC23B expression in the CDA II lines. RNA sequencing of iEPCs pre- and post-differentiation identified novel pathways involved in disease pathogenesis. After transducing the iEPCs with a lentiviral vector expressing SEC23B, we observed a significant decrease in binucleated cells and an increase in terminally differentiated cells. Our results demonstrate that iEPCs can be successfully generated from patients with rare red cell diseases and that CDA II disease modeling using iEPCs is viable for studying disease mechanisms and evaluating gene therapy vectors.
2023-06-29 | New Cases and Mutations in SEC23B Gene Causing Congenital Dyserythropoietic Anemia Type II.
Congenital dyserythropoietic anemia type II (CDA II) is an inherited autosomal recessive blood disorder which belongs to the wide group of ineffective erythropoiesis conditions. It is characterized by mild to severe normocytic anemia, jaundice, and splenomegaly owing to the hemolytic component. This often leads to liver iron overload and gallstones. CDA II is caused by biallelic mutations in the SEC23B gene. In this study, we report 9 new CDA II cases and identify 16 pathogenic variants, 6 of which are novel. The newly reported variants in SEC23B include three missenses (p.Thr445Arg, p.Tyr579Cys, and p.Arg701His), one frameshift (p.Asp693GlyfsTer2), and two splicing variants (c.1512-2A>G, and the complex intronic variant c.1512-3delinsTT linked to c.1512-16_1512-7delACTCTGGAAT in the same allele). Computational analyses of the missense variants indicated a loss of key residue interactions within the beta sheet and the helical and gelsolin domains, respectively. Analysis of SEC23B protein levels done in patient-derived lymphoblastoid cell lines (LCLs) showed a significant decrease in SEC23B protein expression, in the absence of SEC23A compensation. Reduced SEC23B mRNA expression was only detected in two probands carrying nonsense and frameshift variants; the remaining patients showed either higher gene expression levels or no expression changes at all. The skipping of exons 13 and 14 in the newly reported complex variant c.1512-3delinsTT/c.1512-16_1512-7delACTCTGGAAT results in a shorter protein isoform, as assessed by RT-PCR followed by Sanger sequencing. In this work, we summarize a comprehensive spectrum of SEC23B variants, describe nine new CDA II cases accounting for six previously unreported variants, and discuss innovative therapeutic approaches for CDA II.
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2025-12-25 | MMS22L is a novel key actor of normal and pathological erythropoiesis.
The emergence of next-generation sequencing techniques has led to the genetic characterization of numerous congenital erythroid disorders, emphasizing crucial pathways in both normal and pathological erythropoiesis. In this study, whole exome sequencing of a single patient with atypical congenital pure red cell aplasia revealed a mutation in the CDAN1 gene, typically associated with congenital dyserythropoietic anemia type 1 (CDAI), together with a previously unreported mutation in the MMS22L gene. Combined mms22l and cdan1 haploinsufficiency results in severe anemia in a zebrafish model. In human erythroid progenitors, loss of MMS22L leads to proliferation and differentiation arrest associated with activation of the p53 pathway and global epigenetic alterations, showing that MMS22L plays an indispensable role in erythropoiesis. Furthermore, MMS22L and CDAN1 are involved in the same protein complex whose nuclear import is mediated by the importin 4 (IPO4) protein, and MMS22L nuclear import is impaired in CDAI patients due to a defective interaction between CDAN1 and IPO4. Overall, through the genetic description of a single case characterized by digenic inheritance, we identified MMS22L as a novel key factor in erythropoiesis and brought new insights into normal erythropoiesis regulation and CDAI pathophysiology.
2024-11-05 | Abatacept Abrogates the Risk of Acute GvHD in Both Matched and Mismatched Transplantation for Haemoglobinopathies and Bone Marrow Failure
Introduction: Allogeneic hematopoietic stem cell transplantation [HCT] is a well-established curative therapy for hemoglobinopathies and bone marrow failure syndromes [BMF]. Advances in conditioning regimens and prophylaxis have reduced the incidence of graft versus host disease [GvHD]. However, GVHD remains the most important factor of morbidity and impacts long-term outcomes. This is particularly important with the advent of HLA-mismatched and haploidentical HCT leading to universal availability of curative treatment for these indications where there is no advantage for a graft versus leukaemia effect. Abatacept is a fusion protein cytotoxic T cell-lymphocyte-4-immunoglobulin [CTLA4-Ig] that induces co-stimulatory blockade of CD80 and CD86 on antigen presenting cells modulating T-cell activation. Abatacept has been shown to result in a reduction of severe GvHD and improved outcomes in the malignant HCT setting [Watkins et al 2021]. Aims: We hypothesised that the addition of abatacept for 6 months to GvHD prophylaxis would result in a reduced rate of acute GVHD in children undergoing HCT for hemoglobinopathies and BMF with improved outcomes. Methods: Between June 2023 and June 2024, 35 consecutive T cell replete HCT received abatacept prophylaxis: 10 mg/kg [day -1, day +5, day +14, day +28, day +60, day +90, day +120, day +150. Results were compared to HCT outcomes from the previous four years. 16 procedures were matched related, 9 matched unrelated, 5 matched unrelated and 5 haploidentical HCT. 15 children had sickle cell disease, 8 transfusion dependent thalassemia, 4 for Diamond-Blackfan anemia, 2 Fanconi anemia, 2 congenital dyserythropoietic anemia and 4 for severe aplastic anemia. The outcomes were compared to a historical control group of 66 consecutive HCT between January 2020 and May 2023 at the same institution using the same conditioning regimens but without abatacept prophylaxis. The median age was the 11 years of age in both groups (abatacept group range 2-18 years and control group 2-19 years). The source of stem cells consisted of 31 bone marrow and 4 PBSC in the abatacept group whereas the control group had no PBSC use. The median follow-up was 6.4 months (0.95 - 12.9) for the abatacept group and 15.9 months for the control group (1.5 - 42.5). Estimates for the probability were calculated using the Kaplan-Meier statistical approach. Results: All patients in the abatacept group engrafted and are alive whereas there were 2 cases of graft failure (3%) and 3 deaths (4.5%) in the control group. Median neutrophil engraftment was 16.5 days (11-28) in the abatacept group and 13 days (9-29). The probability of acute GVHD grade II-IV was significantly lower in the abatacept group: 6.6% (2 cases) versus 39.7% in the control group (26 cases), p <0.001. There were no cases of acute GvHD grade III-IV in the abatacept group whereas there were 11 (16.8%) of which one was grade 4 in the control group, P 0.016. This was associated with a median cessation of immunosuppression of 180 days (108-295) in the abatacept group (n = 13) versus 216 days (106-523) in the control group. The OS and EFS at 1 year was 100% for the abatacept group whereas the 96.8% and 93.6% respectively for the control group. Conclusion: Abatacept reduces the risk of grade II-IV acute GVHD in both matched and mismatched pediatric HCT for non-malignant disorders including hemoglobinopathies and bone marrow failure syndromes. Further, abatacept resulted in a reduction in the duration of immunosuppression. It is particularly effective in abrogating the risk of severe acute GvHD. It was well tolerated with no associated toxicity with its use. References: WatkinB, Qayed M, McCracken C, et al. Phase II trial of costimulation blockade with abatacept for prevention of acute GVHD. J Clin Oncol. 2021. ;39(17):1865-1877.
2021-09-15 | Majeed Syndrome: A Review of the Clinical, Genetic and Immunologic Features.
Majeed syndrome is a multi-system inflammatory disorder affecting humans that presents with chronic multifocal osteomyelitis, congenital dyserythropoietic anemia, with or without a neutrophilic dermatosis. The disease is an autosomal recessive disorder caused by mutations in LPIN2, the gene encoding the phosphatidic acid phosphatase LIPIN2. It is exceedingly rare. There are only 24 individuals from 10 families with genetically confirmed Majeed syndrome reported in the literature. The early descriptions of Majeed syndrome reported severely affected children with recurrent fevers, severe multifocal osteomyelitis, failure to thrive, and marked elevations of blood inflammatory markers. As more affected families have been identified, it has become clear that there is significant phenotypic variability. Data supports that disruption of the phosphatidic acid phosphatase activity in LIPIN2 results in immune dysregulation due to aberrant activation of the NLRP3 inflammasome and overproduction of proinflammatory cytokines including IL-1β, however, these findings did not explain the bone phenotype. Recent studies demonstrate that LPIN2 deficiency drives pro-inflammatory M2-macrophages and enhances osteoclastogenesis which suggest a critical role of lipin-2 in controlling homeostasis at the growth plate in an inflammasome-independent manner. While there are no approved medications for Majeed syndrome, pharmacologic blockade of the interleukin-1 pathway has been associated with rapid clinical improvement.
2015-02-24 | New insights into iron regulation and erythropoiesis
Purpose of review Iron homeostasis and erythropoiesis regulate each other to ensure optimal delivery of oxygen and iron to cells and tissues. Defining the mechanisms of this crosstalk is important for understanding the pathogenesis of common conditions associated with disordered iron metabolism and erythropoiesis. Recent findings Stress erythropoiesis causes suppression of hepcidin to increase iron availability for hemoglobin synthesis. The erythroid hormone erythroferrone (ERFE) was identified as the mediator of this process. ERFE and additional candidates (TWSG1 and GDF15) may also mediate hepcidin suppression in ineffective erythropoiesis. Several mechanisms by which iron regulates erythropoiesis were also recently identified. Iron deficiency suppresses erythropoietin production via the IRP1–HIF2α axis to prevent excessive iron usage by erythropoiesis during systemic iron restriction. Iron restriction also directly impairs erythroid maturation by inhibiting aconitase, and this can be reversed by the administration of the aconitase product isocitrate. Another novel target is GDF11, which is thought to autoinhibit erythroid maturation. GDF11 traps show promising pharmacologic activity in models of both ineffective erythropoiesis and iron-restricted anemia. Summary This review summarizes exciting advances in understanding the mechanisms of iron and erythropoietic regulation, and development of novel therapeutic tools for disorders resulting from dysregulation of iron metabolism or erythropoiesis.
2012-09-26 | Naturally Occurring Anti-Band 3 Antibodies in Clearance of Senescent and Oxidatively Stressed Human Red Blood Cells
Naturally occurring anti-band 3 antibodies (anti-band 3 NAbs) are directed against the 55-kDa chymotryptic fragment of the anion transport protein (band 3) of red blood cells (RBCs). They bind to senescent and oxidatively stressed RBCs and induce their selective clearance. These IgG NAbs exist at low concentrations, and have a weak affinity that prevents them from actively recruiting second binding sites. Cellular senescence or oxidative damage induces a cascade of biochemical events that results in the detachment of band 3 from the cytoskeleton and in clustering of band 3 protein by bound hemichromes and Syk kinase. Clustered band 3 proteins allow bivalent binding of anti-band 3 NAbs. Bivalently bound anti-band 3 NAbs have the unique capacity to stimulate C3b deposition by preferentially generating C3b2-IgG complexes, which act as potent C3 convertase precursors of the alternative complement pathway. Antibody binding not only to clustered, but also to oligomerized band 3 protein further increases if the human plasma also contains induced anti-lactoferrin antibodies. These bind to the polylactosaminyl oligosaccharide, a carbohydrate that exists in lactoferrin and in the 38-kDa fragment of band 3 protein. Anti-lactoferrin antibodies are found primarily in plasma of patients with autoimmune diseases and who have anti-neutrophil cytoplasmic antibodies (ANCA).Natürlicherweise vorkommende Anti-Bande-3-Antikörper (Anti-Bande-3-NAbs) sind gegen das chymotrypti-sche 55-kDa-Fragment des Anionenaustauschproteins der roten Blutkörperchen (RBCs) (Bande 3) gerichtet, binden an alte und oxidativ geschädigte RBCs und induzieren deren selektive Phagozytose. Diese NAbs sind IgG-Immunglobuline und haben eine schwache Affinität, welche sie daran hindert, aktiv Zweitbindungsstellen zu rekrutieren. Zelluläre Alterung oder oxidative Schädigungen induzieren eine Kaskade von biochemischen Vorgängen, die in der Ablösung der Bande-3-Proteine vom Zytoskelett resultieren und die Verklumpung von Bande 3 in der Membran durch die Bindung von Hemichromen und Syk-Kinase begünstigen. Verklumpte Bande-3-Proteine erlauben eine bivalente Bindung der Anti-Bande-3-NAbs. Bivalent gebundene Anti-Bande-3-NAbs haben die Fähigkeit, die C3b-Deposition zu stimulieren indem sie präferentiell C3b2-IgG bilden, die als potente Vorläufer von alternativen C3-Konvertasen wirken. Die Antikörper-Bindung nicht nur an verklumpte, sondern bereits an oligomerisierte Bande-3-Proteine steigt weiter an, wenn humanes Plasma auch induzierte Anti-Laktoferrin-Antikörper enthält, die an das Polylactosylaminyl-Kohlehydrat binden, das in Laktoferrin vorkommt aber auch im 38-kDa-Fragment des Bande-3-Proteins. Anti-Laktoferrin-Antikörper treten bevorzugt im Plasma von Patienten mit Autoimmunkrankheiten auf, insbesondere solchen, die sich durch anti-neutrophile zytoplasmatische Antikörper (ANCA) auszeichnen.
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