RARE DISEASE
Diamond-Blackfan anemia
Diamond-Blackfan anemia
Diamond-Blackfan anemia
Synonyms: Congenital PRCA, Congenital pure red cell aplasia, Diamond-Blackfan anemia syndrome
Synonyms: Congenital PRCA, Congenital pure red cell aplasia, Diamond-Blackfan anemia syndrome
Synonyms: Congenital PRCA, Congenital pure red cell aplasia, Diamond-Blackfan anemia syndrome
Drug discovery
5
drugs
With orphan designations
Overview
Diamond-Blackfan anemia (DBA) is a rare inherited bone marrow failure syndrome characterized by defective erythropoiesis, congenital anomalies (craniofacial, thumb, cardiac), and increased cancer risk. Caused by mutations in ribosomal protein genes (RPS19, RPL5, etc.), it typically presents with macrocytic anemia in infancy. Autosomal dominant inheritance occurs in 45% of cases, while 55% arise from de novo mutations. Diagnosis requires exclusion of acquired causes and genetic testing [1][6][12].
Therapies
First-line: Corticosteroids (80% initial response; long-term adverse effects limit use) [3][8][17]
Transfusion-dependent: Chronic red cell transfusions with iron chelation (deferasirox/deferoxamine) [8][13][16]
Definitive cure: HLA-matched hematopoietic stem cell transplantation (HSCT; >90% survival in children) [6][13][17]
Categories: rare developmental anomalies during embryogenesis, rare genetic diseases, rare hematological diseases, rare inborn errors of metabolism, rare neoplastic diseases, rare neurological diseases, rare otorhinolaryngological diseases, rare surgical maxillo-facial diseases, rare transplant-related disorders
Research Papers
394 drug discovery papers about Diamond-Blackfan anemia, with 2 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
394 drug discovery papers about Diamond-Blackfan anemia, with 2 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
proteins
2025-10-25 | Congenital Anemia Due to Erythropoietin Gene Mutation Presenting With Diamond-Blackfan Anemia-like features.
Diamond-Blackfan anemia (DBA) is an inherited hypoplastic anemia, caused by mutations in ribosomal protein genes. Other mutations such as mutations in the erythropoietin (EPO) gene can lead to DBA-like (DBAL) through impairment of erythropoiesis. We present a 9-year-old patient with normocytic, normochromic, transfusion-dependent anemia since birth and reticulocytopenia. Bone marrow biopsies showed erythroid hypoplasia thereby excluding myelodysplasia and iron deficiency. Whole-exome sequencing revealed a homozygous mutation (c.530G>A; p.R177Q) in the EPO gene, which encodes a protein involved in erythroid progenitor-cell proliferation, confirmed the diagnosis of the DBAL. Diagnosis of congenital anemias has been complicated by their similar characteristics with DBA, but genetic testing is important in detecting rare causes of these disorders. This diagnosis enabled us to use recombinant human EPO therapy which reduced the need for blood transfusion.
2024-05-30 | Reduced toxicity conditioning for hematopoietic stem cell transplantation in children with Diamond-Blackfan anemia
Not available.
2024-05-13 | Understanding complex disease-related mechanisms: Rational therapies for Diamond-Blackfan anaemia.
The rich history surrounding Diamond-Blackfan anaemia (DBA), originally described in 1938 as congenital hypoplastic anaemia2 reflects the evolution of paediatric haematology. In their paper, the authors1 present the results of a clinical trial using the thrombopoietin-mimetic agent eltrombopag to treat red cell failure in DBA. A low response rate belies the importance of this work. Commentary on: Duncan et al. Treatment of refractory/relapsed Diamond-Blackfan anaemia with eltrombopag. Br J Haematol 2024;204:2077-2085.
2024-03-07 | Establishment of a Diamond-Blackfan anemia like model in zebrafish.
Anemia is defined as a lack of erythrocytes, low hemoglobin levels, or abnormal erythrocyte morphology. Diamond-Blackfan anemia (DBA) is a rare and severe congenital hypoplastic anemia that occurs due to the dominant inheritance of a ribosomal protein gene mutation. Even rarer is a case described as Diamond-Blackfan anemia like (DBAL), which occurs due to a loss-of-function EPO mutation recessive inheritance. The effective cures for DBAL are bone marrow transfusion and treatment with erythropoiesis-stimulating agents (ESAs). To effectively manage the condition, construction of DBAL models to identify new medical methods or screen drugs are necessary. Here, an epoa-deficient mutant zebrafish called epoaszy8 was generated to model DBAL. The epoa-deficiency in zebrafish caused developmental defects in erythroid cells, leading to severe congenital anemia. Using the DBAL model, we validated a loss-of-function EPO mutation using an in vivo functional analysis and explored the ability of ESAs to alleviate congenital anemia. Together, our study demonstrated that epoa deficiency in zebrafish leads to a phenotype resembling DBAL. The DBAL zebrafish model was found to be beneficial for the in vivo assessment of patient-derived EPO variants with unclear implications and for devising potential therapeutic approaches for DBAL.
2023-06-20 | Targeting of Calbindin 1 rescues erythropoiesis in a human model of Diamond Blackfan anemia.
Diamond Blackfan anemia (DBA) is an inherited bone marrow failure syndrome characterized by congenital anomalies, cancer predisposition and a severe hypo-proliferative anemia. It was the first disease linked to ribosomal dysfunction and >70 % of patients have been identified to have a haploinsufficiency of a ribosomal protein (RP) gene, with RPS19 being the most common mutation. There is significant variability within the disease in terms of phenotype as well as response to therapy suggesting that other genes contribute to the pathophysiology and potential management of this disease. To explore these questions, we performed a genome-wide CRISPR screen in a cellular model of DBA and identified Calbindin 1 (CALB1), a member of the calcium-binding superfamily, as a potential modifier of the disordered erythropoiesis in DBA. We used human derived CD34+ cells cultured in erythroid stimulating media with knockdown of RPS19 as a model for DBA to study the effects of CALB1. We found that knockdown of CALB1 in this DBA model promoted erythroid maturation. We also noted effects of CALB1 knockdown on cell cycle. Taken together, our results reveal CALB1 is a novel regulator of human erythropoiesis and has implications for using CALB1 as a novel therapeutic target in DBA.
cell therapies
2026-05-09 | Germline TP53 Mutations Causing Diamond-Blackfan Anemia: A French Report.
Diamond-Blackfan anemia is a rare congenital erythroblastopenia typically caused by mutations in ribosomal protein genes. Recently, gain-of-function mutations in TP53 have been identified as a novel cause of Diamond-Blackfan anemia. We report two French patients who both harbored a heterozygous TP53 deletion (NM_000546.5: c.1077delA; p.(Ser362AlafsTer8)). They exhibited normocytic anemia, transient neutropenia at presentation, and distinct neurological impairments. Neither patient responded to a corticosteroid trial. One patient underwent hematopoietic stem cell transplantation from a matched sibling donor and remained transfusion-independent at last follow-up. This study emphasizes the complexity of TP53-associated Diamond-Blackfan anemia syndrome and presents the only patient to date cured by hematopoietic stem cell transplantation.
2026-04-19 | Spleno-Medullary Progenitor Cell Transplantation (SMPT): A Comprehensive, Mechanistically Grounded, and Empirically Falsifiable Theoretical Framework with Integrated p53-MDM2 Dynamics, Expanded Dynamic Stability Analysis, Global Sensitivity Analysis, Bayesian Inference, and Quantitative Risk Assessment for Autologous Restoration of Erythropoiesis in Severe Aplastic Anemia, Diamond-Blackfan Anemia, and Hereditary Bone Marrow Failure Syndromes
We present a rigorously upgraded and extensively detailed in silico theoretical framework for Spleno-Medullary Progenitor Cell Transplantation (SMPT), an autologous cellular intervention hypothesized to restore effective erythropoiesis in severe aplastic anemia (SAA), Diamond-Blackfan anemia (DBA), and a spectrum of hereditary bone marrow failure syndromes. The framework incorporates a dedicated fifth compartment modeling p53 activity with explicit biochemical kinetics derived from the p53-MDM2 negative feedback loop and ribosomal stress sensing (RPL5/RPL11). The five-dimensional deterministic/stochastic ordinary/stochastic differential equation (ODE/SDE) system is subjected to comprehensive analytical stability analysis, including derivation of the full Jacobian matrix, analytical equilibrium solutions, Lyapunov-based global stability proofs, bifurcation analysis with respect to engraftment efficiency, and phase-plane projections. Global sensitivity analysis (Sobol indices up to second-order, N=10^4 Saltelli samples across six key parameters: β, κ, η, δ, γ, λ) and time-dependent sensitivity heatmaps are presented. Bayesian inference, optimized via a steady-state algebraic surrogate for MCMC feasibility (4 chains, 2000 draws), yielded robust posterior estimates with strict convergence (R̂ ≤ 1.01, ESS >800). Monte-Carlo uncertainty quantification (N=5000 SDE trajectories) predicts robust restoration of normalized RBC counts to R(200)=209.37 under nominal SMPT conditions (β=0.35). A branching-process model estimates the probability of ex-vivo acquisition of a myeloid driver mutation at 3.0×10^{-6} per progenitor cell. Every central claim is formulated as a Popperian-falsifiable hypothesis, and all computational outputs are fully reproducible via the complete Python code provided in the Supplementary Information (with explicit random seeds, tolerance settings, and modular syndrome-specific parameter overrides). This work establishes a quantitative, evidence-anchored, and mechanistically explicit foundation for future experimental validation of niche-engineered autologous therapies across inherited and acquired bone marrow failure syndromes.
2026-04-10 | Spleno-Medullary Progenitor Cell Transplantation (SMPT): A Mechanistically Grounded, Empirically Falsifiable Theoretical Framework for Autologous Restoration of Erythropoiesis in Severe Aplastic Anemia and Diamond-Blackfan Anemia
We introduce a novel in silico conceptual framework for spleno-medullary progenitor cell transplantation (SMPT), positing it as a targeted autologous intervention designed to restore red blood cell (RBC) production in two severe bone marrow failure syndromes: aplastic anemia (SAA) and Diamond-Blackfan anemia (DBA). The core hypothesis of SMPT is the strategic exploitation of the spleen's known, albeit often latent, reservoir of stress-adapted erythroid progenitors. These progenitors would be harvested, robustly expanded ex-vivo, and subsequently re-infused into a specifically cytokine-primed bone marrow niche. Mechanistically, this approach is hypothesized to circumvent the T-cell-mediated autoimmune destruction of hematopoietic stem and progenitor cells (HSPCs) characteristic of SAA. Furthermore, in DBA, SMPT proposes a potential mitigation of the ribosomal biogenesis defects and subsequent p53-mediated erythroid apoptosis through an as-yet-uncharacterized niche-mediated compensatory mechanism, thereby addressing the fundamental defect while eliminating allogeneic transplantation risks.A four-compartment deterministic/stochastic ordinary/stochastic differential equation (ODE/SDE) model, rigorously parameterized from comprehensive peer-reviewed kinetic data and subjected to advanced computational analyses—including global sensitivity analysis (Sobol indices, \(N=10\,000\) Monte Carlo samples), Bayesian posterior inference, and Monte-Carlo uncertainty quantification (\(N=5000\) simulations)—predicts a restoration of normalized RBC counts from a near-zero baseline to \(R(200)\approx 247.72\) (arbitrary units, representing physiological levels) within 200 days post-intervention, under the stated model assumptions. Crucially, all mathematical derivations, parameter values, supporting Python code, and simulated outputs are entirely computationally reproducible. This manuscript rigorously establishes a mechanistically grounded and empirically falsifiable theoretical foundation for future experimental validation of niche-engineered autologous cellular therapies in challenging bone marrow failure syndromes. Each central claim is explicitly formulated as a testable hypothesis, strictly adhering to Popperian falsifiability criteria to facilitate robust scientific inquiry.
2026-04-10 | Umbilical cord blood transplantation in children with Diamond-Blackfan anemia.
Diamond-Blackfan anemia (DBA) is a rare inherited bone marrow failure syndrome characterized by macrocytic anemia and physical malformations. The only available curative treatment for patients with DBA is hematopoietic cell transplantation (HCT). Previous studies have included umbilical cord blood transplantation (UCBT) alongside other graft sources. We conducted a retrospective analysis of 41 pediatric patients with DBA who underwent related or unrelated UCBT between 1994 and 2023, using data from the Eurocord/EBMT registry. Twenty patients received related and 21 received unrelated single UCBT. Most patients received myeloablative conditioning and were transplanted after 1999. In related UCBT, median follow-up was 144.8 months, neutrophil engraftment at day +42 was 100% and 5-year overall survival (OS) was also 100%. In unrelated UCBT, median follow-up was 34 months, neutrophil engraftment at day +42 was 90%, and 5-year OS was 66%. The incidence of acute graft-versus-host disease (GvHD) was considerably higher among unrelated UCBT recipients. The incidence of chronic GvHD was similar between the two cohorts; however, extensive disease was more common after unrelated UCBT. UCBT from an HLA-identical sibling should be considered for DBA patients given the favorable short- and long-term outcomes. For the remaining patients, unrelated UCBT could be considered after individualized risk-benefit assessement.
2026-03-26 | Spleno-Medullary Progenitor Cell Transplantation (SMPT): A Mechanistically Grounded Theoretical Framework for Autologous Restoration of Erythropoiesis in Severe Aplastic Anemia and Diamond-Blackfan Anemia
We present a novel in silico conceptual framework for spleno-medullary progenitor cell transplantation (SMPT) as a targeted autologous intervention to restore red blood cell (RBC) production in severe aplastic anemia (SAA) and Diamond-Blackfan anemia (DBA). The approach hypothesizes exploitation of the spleen's latent reservoir of stress-adapted erythroid progenitors—harvested, ex-vivo expanded, and re-infused into a cytokine-primed marrow niche. This may circumvent autoimmune HSPC destruction in SAA and potentially mitigate ribosomal biogenesis defects in DBA through niche-mediated compensatory mechanisms, while eliminating allogeneic risks.A four-compartment deterministic/stochastic ODE/SDE model, parameterized from peer-reviewed kinetic data and subjected to global sensitivity analysis (Sobol indices), Bayesian posterior inference, and Monte-Carlo uncertainty quantification, predicts restoration of normalized RBC counts to R(200)≈247.72 (arbitrary units) from near-zero baseline under stated assumptions. All derivations, parameters, Python code, and simulation outputs are computationally reproducible. This manuscript provides a mechanistically grounded theoretical foundation for future experimental validation of niche-engineered autologous therapies in bone marrow failure syndromes.
small molecules
2026-07-23 | Ribosome biogenesis and selective translational control as oncogenic vulnerabilities in hematologic malignancies
The translation of the transcriptome into a functional proteome is not a passive readout of mRNA abundance but a primary regulatory layer that actively shapes the oncogenic landscape. In hematologic malignancies, convergent oncogenic signaling pathways, including MYC, PI3K/AKT/mTOR, and tyrosine kinase fusions, directly reprogram the translational apparatus, driving a qualitative shift toward the selective synthesis of pro-survival, proliferative, and stemness-associated proteins. This deregulated program is orchestrated through multiple interconnected axes: the accelerated biogenesis of ribosomes within the nucleolus, the assembly of the eIF4F initiation complex, the activation of stress-adaptive programs like the integrated stress response (ISR), and a sophisticated layer of epitranscriptomic, tRNA, and RNA-binding protein-mediated regulation. Hematologic cancers provide a uniquely informative framework for deconstructing these processes, illustrated by inherited ribosomopathies, such as Diamond-Blackfan anemia syndrome and Shwachman-Diamond syndrome, which resolve the paradox of how ribosomal insufficiency can evolutionarily transition into malignant transformation. Beyond pathogenesis, the translational machinery represents a rich landscape of actionable vulnerabilities. Pharmacological targeting of RNA Polymerase I, eIF4A, and the ISR has demonstrated selective antitumor activity and synergistic potential with established therapies, including BCL-2 inhibition. This review synthesizes mechanistic and clinical evidence to position the ribosome as an active regulatory node rather than a passive decoding machine. We further examine the challenges facing the field, including translational plasticity under therapeutic pressure, the lack of validated companion biomarkers, and the emerging role of translational control in modulating anti-tumor immunity. Ultimately, we argue that defining the disease-specific translational states of leukemia and lymphoma is essential for the next generation of precision oncology, moving beyond genomic landscapes toward a proteomic-centered understanding of malignancy.
2026-06-30 | Factors determining successful allogeneic hematopoietic stem cell transplantation in children with inherited bone marrow failure syndromes
Introduction. Inherited bone marrow failure syndromes (IBMFS) constitute a heterogeneous group of rare genetic disorders associated with impaired hematopoiesis, congenital anomalies, and a high risk of transformation to myelodysplastic syndrome and acute myeloid leukemia. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative treatment for IBMFS. Aim: to identify factors determining the efficacy of allo-HSCT in pediatric patients with IBMFS. Materials and methods. This study analyzed data from 61 patients with IBMFS who had undergone allo-HSCT between 2005 and 2025 at the R.M. Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantation. Results. The median follow-up was 24 months. The overall survival (OS) at 1, 3, and 5 years post-transplantation was 88%, 85%, and 81%, respectively. The lowest 5-year OS was observed in the Fanconi anemia (47%) and Diamond–Blackfan anemia (86%) groups, whereas in the patients with other IBMFS the 5-year OS reached 100% (p = 0.003). Factors associated with improved survival included age younger than 5 years at transplantation (100% vs. 68%; p = 0.009), the use of myeloablative conditioning regimens (100% vs. 64.5%; p = 0.002), the use of post-transplant cyclophosphamide (PTCy) for graft-versus-host disease (GVHD) prophylaxis (100% vs. 67%; p = 0.02), and successful engraftment (88% vs. 33%; p = 0.002). GVHD prophylaxis regimens without calcineurin inhibitors were associated with a lower incidence of grade II–IV acute GVHD (11% vs. 44%; p = 0.03) and a reduced need for switching immunosuppression (5% vs. 35%; p = 0.02). Donor type and degree of HLA matching did not significantly affect survival. Conclusion. Allo-HSCT is a highly effective treatment for children with IBMFS, providing a 5-year OS of 81%. The best outcomes are achieved with allo-HSCT performed at an early age (under 5 years), the use of myeloablative conditioning regimens (when not contraindicated), and with the addition of PTCy to GVHD prophylaxis. The lowest survival was observed in the patients with Fanconi anemia, highlighting the need for further refinement of treatment protocols for this patient group. PTCy-based GVHD prophylaxis regimens without calcineurin inhibitors reduce the incidence of acute GVHD and improve the tolerability of immunosuppression.
2026-06-30 | Recovery of erythropoiesis in Diamond–Blackfan anemia using eltrombopag in a cellular model: interim study results
Introduction. Diamond–Blackfan anemia (DBA) is a rare congenital bone marrow failure syndrome classified as a ribosomopathy and characterized by selective aplasia of the erythroid lineage. Despite advances in understanding its pathogenesis, treatment options are still limited, and a significant proportion of patients remain transfusion-dependent. Aim: to evaluate the effect of eltrombopag on the colony-forming potential of bone marrow erythroid progenitors in DBA patients in vitro. Materials and methods. The study included 10 patients with genetically confirmed DBA and 7 healthy donors. Bone marrow mononuclear cells were cultured in a methylcellulose medium supplemented with eltrombopag at concentrations of 13 and 26 μg/mL. Results. In vitro, the addition of eltrombopag to bone marrow cell cultures from the patients with DBA resulted in a significant increase in the number of erythroid colonies compared to control cultures without the drug. For early erythroid progenitors, a statistically significant increase in the number of colonies was observed. Conclusion. These interim results suggest that eltrombopag may be considered a potential stimulator of erythropoiesis in DBA and support the need for further research in larger cohorts in order to clarify the clinical significance of the observed effects.
2026-06-28 | Danazol in Contemporary Clinical Practice: A Comprehensive Review of Pharmacology, Therapeutic Applications, and Emerging Roles in Hematological Disorders
Danazol, a synthetic androgen-derived steroid with distinctive structural and pharmacological properties, has maintained clinical relevance for over four decades despite significant therapeutic advances in its primary indications. Originally developed for the management of endometriosis, this multifaceted compound has demonstrated remarkable versatility across diverse medical specialties, extending its utility to hereditary angioedema, immune thrombocytopenia, and various bone marrow failure syndromes. The compound's unique mechanism of action, encompassing anti-gonadotropic effects, direct steroidogenesis inhibition, immunomodulation, and telomerase activation, explains its efficacy across seemingly disparate pathological conditions. This comprehensive review examines danazol's pharmacological foundations, clinical applications, adverse effect profile, and emerging therapeutic roles, with particular emphasis on its resurgence in hematological practice. The pharmacokinetic properties of danazol, including its oral bioavailability, extensive tissue distribution, and hepatic metabolism, underpin its clinical utility while simultaneously necessitating careful monitoring for drug interactions and toxicity. Recent evidence supporting danazol's efficacy in corticosteroid-refractory immune thrombocytopenia, Diamond-Blackfan anemia, and telomere biology disorders has revitalized interest in this established agent, particularly in resource-constrained settings where novel biological therapies remain inaccessible. The compound's manageable adverse effect profile, cost-effectiveness, and oral administration render it an attractive therapeutic option for appropriately selected patients, though the interprofessional healthcare team must remain vigilant regarding potential hepatic, cardiovascular, and androgenic effects. This review synthesizes current evidence to provide clinicians with a comprehensive framework for the rational use of danazol in contemporary practice, emphasizing the importance of individualized therapy, vigilant monitoring, and collaborative care coordination.
2026-06-23 | Metadichol as a Coordinated Activator of Core Cellular Machinery Part II—From Inhibition to Activation: Metadichol Is the First Coordinated Activator of the 47-Gene 60S Ribosomal Protein Repertoire
Background. Metadichol® (Nano-Policosanol; Nanorx Inc.) is a nano-emulsion of food-derived very-long-chain primary alcohols (C26–C36) that acts as a Vitamin D Receptor (VDR) inverse agonist at picomolar to nanomolar concentrations. Prior peer-reviewed work has documented its regulation of all 49 nuclear receptors, all 7 sirtuins, Toll-like receptors, and the Yamanaka pluripotency factors. The 60S large ribosomal subunit—the catalytic engine of the ribosome housing the peptidyl-transferase centre—is encoded by 47 ribosomal protein genes (RPL/RPLP) that also perform extraribosomal roles in p53 surveillance, inflammatory mRNA silencing, and developmental patterning. Whether a single food-derived compound can coordinately regulate this entire repertoire has not been tested. Methods. Human PBMCs were isolated by Histopaque-1077 density-gradient centrifugation and treated for 24 h with Metadichol at 0.1 pg/mL, 1 pg/mL, 100 pg/mL, 1 ng/mL, and 100 ng/mL alongside untreated controls. Total RNA was extracted (TRIzol), reverse-transcribed (500 ng; PrimeScript), and all 47 large-subunit RPL/RPLP genes were quantified by SYBR-Green qRT-PCR (39 cycles; 60 °C annealing) using gene-specific validated primers. Relative expression was computed by the 2^−ΔΔCq method with GAPDH as reference; significance by one-way ANOVA with Dunnett's test. Results. All 47 large-subunit ribosomal protein genes were significantly up-regulated by Metadichol relative to untreated control, but in a strikingly coherent, non-monotonic (biphasic) manner. At the lowest dose (0.1 pg/mL) 44 of 47 genes were suppressed below control (mean 0.53-fold), whereas activation rose to a sharp maximum at 1 ng/mL—where 33 of 47 genes reached their individual peak (mean 2.27-fold)—before partial relaxation at 100 ng/mL. The largest single responses were RPL30 (5.43-fold), RPL24 (4.78-fold), RPL37 (4.31-fold), RPL38 (4.30-fold), RPL34 (4.17-fold), RPL18 (3.92-fold), RPL37A (3.83-fold), and RPL23A (3.80-fold). The p53-axis regulators RPL5, RPL11, and RPL26, the GAIT-complex protein RPL13A, the Hox-selective translator RPL38, and the P-stalk genes RPLP0/RPLP1/RPLP2 were all induced. Hierarchical clustering resolved a dominant "1 ng/mL-peaking" co-regulated module; inter-dose correlation analysis showed the 1 ng/mL and 100 pg/mL profiles were the most concordant (r ≈ 0.52) while the suppressive 0.1 pg/mL profile was weakly correlated with the activating doses (r ≈ 0.25), defining two regulatory regimes. A 47×47 gene–gene correlation matrix revealed broadly positive co-regulation, consistent with a single shared upstream driver rather than gene-by-gene noise. Conclusions. Metadichol produces a stoichiometrically balanced, dose-tuned activation of the entire 60S ribosomal protein gene set in primary human immune cells. To our knowledge this is the first agent shown to coordinately up-regulate the complete large-subunit repertoire, and it runs counter to the existing ribosome pharmacopeia, which is almost entirely inhibitory (mTOR inhibitors, RNA Pol I inhibitors). The uniform direction and tight gene–gene correlation distinguish this from the selective, imbalanced RPL changes that drive ribosomopathies (Diamond–Blackfan anemia, 5q- MDS, T-ALL), and instead resemble the coordinated ribosome-biogenesis program of pluripotent and regenerating cells. A notable RPL5↔RPL11 (5S RNP) asymmetry marks RPL5 as the single most dose-sensitive node. These findings position Metadichol as the first coordinated, balanced transcriptional activator of translational capacity—the directional mirror image, at the level of gene expression, of both ribosomopathy and ribosome-inhibitor drugs—with implications for ribosomopathy, iPSC reprogramming, immune function, and ageing biology.
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.
2026-07-09 | [Inherited bone marrow failure syndromes].
Diamond-Blackfan anemia (DBA) is a classic example of an inherited bone marrow failure syndrome in the category of erythrocyte diseases. DBA mainly occurs due to ribosome dysfunction. In the peripheral blood, reticulocytes are reduced, and in the bone marrow, only erythroid cells are markedly reduced. DBA primarily develops in infants and is often caused by heterozygous allele mutations in ribosomal protein genes. Activation of p53, translation dysfunction, inflammatory signals, and imbalance of hemoglobin/heme synthesis have been shown to contribute to impaired erythropoiesis and decreased red blood cell production. Patients with DBA are primarily treated with steroids; however, half of these patients eventually become unresponsive to long-term steroid treatment and become transfusion-dependent. Hematopoietic cell transplantation is currently the only curative treatment. Recent advances in gene therapy using lentiviral vectors have shown potential in promoting normal hematopoiesis in the treatment of RPS19-deficient DBA.
2026-07-01 | Case study report on diamond-blackfan anemia
Diamond-Blackfan anemia is a rare inherited bone marrow disorder that usually occurs during infancy. It causes reduced production of red blood cells, leading to severe anemia, poor feeding, pallor, lethargy, and poor growth.
2026-06-18 | Generation and characterization of human iPSC line SANi013-A from a Diamond-Blackfan anemia syndrome (DBAS) patient carrying a heterozygous RPS26 c.95-98 duplication variant.
Diamond-Blackfan Anemia Syndrome (DBAS) is a rare inherited bone marrow failure syndrome diagnosed in early childhood, marked by hypoplastic anemia, congenital anomalies, and increased cancer risk. Most cases involve loss-of-function mutations in ribosomal protein genes, disrupting ribosome biogenesis. We generated iPSC line SANi013-A from a patient with a de novo heterozygous RPS26 c.95-98 duplication. Proerythroblasts derived from peripheral blood were reprogrammed using a non-integrating Sendai virus method. The iPSC line SANi013-A displayed a normal karyotype, expressed pluripotency markers, and differentiated into all three germ layers. This line offers a valuable model for studying DBAS pathogenesis, especially erythropoietic defects.
2026-04-03 | Abstract 1168: Development of RT-dPCR-based functional release assays for the RPS19 gene therapy for Diamond-Blackfan anemia.
Abstract Diamond-Blackfan Anemia (DBA) is a congenital ribosomopathy primarily caused by heterozygous loss-of-function mutations in RPS19, a key component of the 40S ribosomal subunit. RPS19 haploinsufficiency disrupts ribosome biogenesis, triggers p53-dependent cellular stress, and impairs the survival of erythroid progenitor cells. Beyond severe anemia, DBA patients exhibit a slightly elevated risk of hematologic and solid malignancies, highlighting a direct link between ribosomal dysfunction and cancer predisposition. Currently, the only curative approach for DBA is allogeneic bone marrow transplantation which is associated with risk of graft failure and graft-versus-host disease. Gene addition using a third-generation self-inactivating lentiviral vector encoding RPS19 (SJEFS-S19 LV) offers a promising strategy to restore functional RPS19 expression in patient hematopoietic stem and progenitor cells (HSPCs) while maintaining genomic safety and avoiding immune toxicities. Preclinical studies demonstrate that SJEFS-S19 LV effectively corrects erythropoietic defects, restores pre-rRNA processing, and generates a polyclonal, genomically stable population of HSPCs. LVs predominantly integrate into open chromatin regions associated with active transcription. To ensure product quality and functional integrity, we developed a reverse transcription digital PCR (RT-dPCR)-based release assay designed to detect and quantify RPS19 transcript originating specifically from the integrated lentiviral vector following transduction. This approach partitions nucleic acid samples into thousands of micro-reactions, enabling absolute quantification with minimal amplification bias. For determining the RPS19 LV functionality, HEK293 RPS19-heterozygous knockout cells were transduced at varying multiplicities of infection (MOI), and total RNA was extracted for one-step RT-dPCR targeting the LV-derived codon-optimized RPS19 sequence. Increasing MOI correlated with higher normalized RPS19 transcript copies per ng genomic DNA, confirming successful vector integration and expression. This assay provides a robust, quantitative measure of functional gene expression, supporting critical quality attribute assessment of SJEFS-S19 LV. This functional assay concept is being translated into a critical release assay for the RPS19 Gene Therapy Drug Product in transduced CD34+ cells. Overall, this assay platform enables precise assessment of vector performance and provides a framework for translating LV gene therapy toward clinical applications in DBA patients, with potential implications for understanding how restoration of ribosomal protein function may impact oncogenic susceptibility. Citation Format: Neshat Masud, Sabina Ranjit, Nana Liu, Madhuri Kalathur, Senthil Bhoopalan, Catherine Willis. Development of RT-dPCR-based functional release assays for the RPS19 gene therapy for Diamond-Blackfan anemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1168.
other
2026-04-01 | RPL34 deficiency establishes a Δ113p53-tunable model of DBA and enables in vivo reclassification of a missense variant
Although large human sequencing studies have proposed RPL34 as a candidate Diamond–Blackfan anemia (DBA) gene, direct in vivo functional evidence and variant-level validation have been lacking. Here, we functionally characterize loss of rpl34 in zebrafish, which recapitulates DBA hallmarks (severe anemia, developmental abnormalities) and activates p53/Δ113p53. In parallel, a precise orthologous knock-in of a reported human RPL34 missense allele (chr4:109546294:G>A) showed no hematopoietic defect in vivo , providing ACMG BS3-consistent functional evidence suggesting a benign impact in vivo ; however, definitive clinical classification will require corroborating human genetic and cellular evidence. Genetic attenuation of p53 or Δ113p53 reduced apoptosis and partially restored erythropoiesis and survival. Δ113p53 knockdown mitigated anemia in additional p53-dependent RP-deficiency models ( rpl18 , rpl17 , rps19 , rps14 ) but not in the p53-independent nop56 model, indicating a context-dependent mechanism. Together, these data establish RPL34 deficiency as a tractable in vivo model of DBA and identify Δ113p53 knockdown as a context-dependent modulator of p53-driven erythropoiesis.
2025-04-29 | Inflammatory pathways and the bone marrow microenvironment in inherited bone marrow failure syndromes.
Inherited bone marrow failure syndromes (IBMFS) are a diverse group of genetic disorders characterized by insufficient hematopoietic cell production due to blood stem cell dysfunction. The most common syndromes are Fanconi Anemia, Diamond-Blackfan Anemia, and Shwachman-Diamond Syndrome. These conditions share a theme of chronically producing pro-inflammatory cytokines such as TNF-α, IL-1β, IL-6, TGF-β, IFN-I, and IFN-γ. Each of these cytokines can impact the bone marrow microenvironment and drive the pathophysiology of IBMFS. This review aims to provide the latest progress in the field regarding the mechanistic underpinnings of inflammation in these IBMFS, as well as the effect of inflammation on the bone marrow microenvironment. A comprehensive understanding of the inflammation in IBMFS will open new avenues for intervention to restore bone marrow stability and improve patient prognosis. Future research must include targeting these mechanisms to develop novel therapies that can potentially mitigate the effects of chronic inflammation in IBMFS.
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.
2024-04-01 | Use of IV immunoglobulin to treat steroid resistant, immune checkpoint inhibitor induced pure red cell aplasia. A case report
Pure Red Cell Aplasia (PRCA) is a condition defined by depleted erythroid precursors on bone marrow biopsy, normocytic normochromic anaemia and reticulocytopenia.1 PRCA is most commonly idiopathically acquired, but it can be congenital, associated with infection or medications such as immune checkpoint inhibitors (ICIs). Nivolumab and ipilimumab are two novel ICIs that promote immune activation against tumour cells via T cell-mediated apoptosis. They are efficacious immunotherapies and are thus licensed for the treatment of many malignancies, including melanoma.2-4 Despite lacking the substantial side effect profile of older cytotoxic agents,3-5 ICIs can cause overactivation of the immune system, leading to immune-related adverse effects against non-cancerous cells.6-7 Immune mediated attack of erythroid precursors causes PRCA. Due to the rarity of PRCA, and the recent introduction of ICIs, few cases of ICI-related PRCA have been reported.8 ICI-induced haematologic toxicity can be fatal and prompt treatment is essential.7 High dose corticosteroids should be used first line, but treatment for steroid-refractory PRCA is challenging and little literature exists to guide therapy. Here we describe a case of immune-mediated PRCA, neutropenia and thrombocytopenia secondary to nivolumab and ipilimumab in a 38 year old woman. She had a history of BRAF V600-mutated melanoma which had been treated by wide local excision, however, five years after treatment she represented with local recurrence and distal metastases, for which she received nivolumab and ipilimumab. 97 days after starting this regime she presented with fatigue, nausea and exertional breathlessness. Blood tests found pancytopenia (Hb 75 g/L, previously 135 g/L, neutrophils 1.1 × 109/L, previously 2.6 × 109/L and platelets 66 × 109/L, previously 186 × 109/L) (Table 1). After 2 weeks of high dose corticosteroids treatment and wean, the neutrophils and platelets normalised but the low Hb and reticulocytopenia persisted. Further investigations were conducted, including bone marrow aspirate and trephine biopsy showed normal granulo- and megakaryopoesis but with absent erythroid islands (Fig. 1), confirmed PRCA. Second-line treatment options included cyclosporin and intravenous immunoglobulin. Due to the fear of melanoma relapse necessitating prompt restart of ICI, the faster acting IVIg was selected. A repeat haemoglobin 11 days later was 120 g/L with a reticulocyte count of 93 × 109/L. Nivolumab monotherapy was restarted 3 weeks after her IVIg without relapse of PRCA. 3 months after her last nivolumab treatment she remains in remission from PRCA and other immune cytopenias. Upon literature search and analysis, only five other described patients with ICI-induced PRCA failed to respond to steroids and were treated with IVIg.8,9 Whilst response rates to second-line ciclosporin are also high, the advantage of IVIg is the rapid response and single dose nature of the treatment. High dose corticosteroids should remain first line therapy for ICI-induced PRCA and we propose that IVIg be used as the treatment of choice for steroid-refractory disease and that ciclosporin is only started as a third-line. We also provide the first evidence that it is possible to re-challenge patients with ICI who go into remission following IVIg salvage.
2024-01-08 | Refractory Pure Red Blood Cell Aplasia Secondary to Major ABO-Incompatible Allogeneic Stem Cell Transplantation Successfully Treated With Daratumumab.
Pure red cell aplasia (PRCA) is a rare hematologic phenomenon that is usually associated with inherited genetic mutations such as in Diamond-Blackfan anemia. However, due to the emergence of allogenic stem cell transplantation in the treatment of various malignant and non-malignant disorders, the incidence of PRCA has increased. PRCA following hematopoietic stem cell transplant (HSCT) is more commonly seen in the setting of a major ABO-incompatible transplant. Treatment of allo-HSCT induced PRCA can be initially supportive as it takes time for the bone marrow to fully recover. However, prolonged and/or failure of the bone marrow to recover, significantly increases patient's risk of iron overload in the setting of frequent transfusions. Iron deposition can potentially lead to severe life-threatening multiorgan involvement which can be fatal. Therefore, earlier recognition and intervention with immunomodulators in patients who undergo frequent transfusions can be beneficial to mitigate this risk. Here, we present a case with severe transfusion-dependent PRCA following major ABO-incompatible allo-HSCT successfully treated with daratumumab.
proteins
2025-10-25 | Congenital Anemia Due to Erythropoietin Gene Mutation Presenting With Diamond-Blackfan Anemia-like features.
Diamond-Blackfan anemia (DBA) is an inherited hypoplastic anemia, caused by mutations in ribosomal protein genes. Other mutations such as mutations in the erythropoietin (EPO) gene can lead to DBA-like (DBAL) through impairment of erythropoiesis. We present a 9-year-old patient with normocytic, normochromic, transfusion-dependent anemia since birth and reticulocytopenia. Bone marrow biopsies showed erythroid hypoplasia thereby excluding myelodysplasia and iron deficiency. Whole-exome sequencing revealed a homozygous mutation (c.530G>A; p.R177Q) in the EPO gene, which encodes a protein involved in erythroid progenitor-cell proliferation, confirmed the diagnosis of the DBAL. Diagnosis of congenital anemias has been complicated by their similar characteristics with DBA, but genetic testing is important in detecting rare causes of these disorders. This diagnosis enabled us to use recombinant human EPO therapy which reduced the need for blood transfusion.
2024-05-30 | Reduced toxicity conditioning for hematopoietic stem cell transplantation in children with Diamond-Blackfan anemia
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2024-05-13 | Understanding complex disease-related mechanisms: Rational therapies for Diamond-Blackfan anaemia.
The rich history surrounding Diamond-Blackfan anaemia (DBA), originally described in 1938 as congenital hypoplastic anaemia2 reflects the evolution of paediatric haematology. In their paper, the authors1 present the results of a clinical trial using the thrombopoietin-mimetic agent eltrombopag to treat red cell failure in DBA. A low response rate belies the importance of this work. Commentary on: Duncan et al. Treatment of refractory/relapsed Diamond-Blackfan anaemia with eltrombopag. Br J Haematol 2024;204:2077-2085.
2024-03-07 | Establishment of a Diamond-Blackfan anemia like model in zebrafish.
Anemia is defined as a lack of erythrocytes, low hemoglobin levels, or abnormal erythrocyte morphology. Diamond-Blackfan anemia (DBA) is a rare and severe congenital hypoplastic anemia that occurs due to the dominant inheritance of a ribosomal protein gene mutation. Even rarer is a case described as Diamond-Blackfan anemia like (DBAL), which occurs due to a loss-of-function EPO mutation recessive inheritance. The effective cures for DBAL are bone marrow transfusion and treatment with erythropoiesis-stimulating agents (ESAs). To effectively manage the condition, construction of DBAL models to identify new medical methods or screen drugs are necessary. Here, an epoa-deficient mutant zebrafish called epoaszy8 was generated to model DBAL. The epoa-deficiency in zebrafish caused developmental defects in erythroid cells, leading to severe congenital anemia. Using the DBAL model, we validated a loss-of-function EPO mutation using an in vivo functional analysis and explored the ability of ESAs to alleviate congenital anemia. Together, our study demonstrated that epoa deficiency in zebrafish leads to a phenotype resembling DBAL. The DBAL zebrafish model was found to be beneficial for the in vivo assessment of patient-derived EPO variants with unclear implications and for devising potential therapeutic approaches for DBAL.
2023-06-20 | Targeting of Calbindin 1 rescues erythropoiesis in a human model of Diamond Blackfan anemia.
Diamond Blackfan anemia (DBA) is an inherited bone marrow failure syndrome characterized by congenital anomalies, cancer predisposition and a severe hypo-proliferative anemia. It was the first disease linked to ribosomal dysfunction and >70 % of patients have been identified to have a haploinsufficiency of a ribosomal protein (RP) gene, with RPS19 being the most common mutation. There is significant variability within the disease in terms of phenotype as well as response to therapy suggesting that other genes contribute to the pathophysiology and potential management of this disease. To explore these questions, we performed a genome-wide CRISPR screen in a cellular model of DBA and identified Calbindin 1 (CALB1), a member of the calcium-binding superfamily, as a potential modifier of the disordered erythropoiesis in DBA. We used human derived CD34+ cells cultured in erythroid stimulating media with knockdown of RPS19 as a model for DBA to study the effects of CALB1. We found that knockdown of CALB1 in this DBA model promoted erythroid maturation. We also noted effects of CALB1 knockdown on cell cycle. Taken together, our results reveal CALB1 is a novel regulator of human erythropoiesis and has implications for using CALB1 as a novel therapeutic target in DBA.
cell therapies
2026-05-09 | Germline TP53 Mutations Causing Diamond-Blackfan Anemia: A French Report.
Diamond-Blackfan anemia is a rare congenital erythroblastopenia typically caused by mutations in ribosomal protein genes. Recently, gain-of-function mutations in TP53 have been identified as a novel cause of Diamond-Blackfan anemia. We report two French patients who both harbored a heterozygous TP53 deletion (NM_000546.5: c.1077delA; p.(Ser362AlafsTer8)). They exhibited normocytic anemia, transient neutropenia at presentation, and distinct neurological impairments. Neither patient responded to a corticosteroid trial. One patient underwent hematopoietic stem cell transplantation from a matched sibling donor and remained transfusion-independent at last follow-up. This study emphasizes the complexity of TP53-associated Diamond-Blackfan anemia syndrome and presents the only patient to date cured by hematopoietic stem cell transplantation.
2026-04-19 | Spleno-Medullary Progenitor Cell Transplantation (SMPT): A Comprehensive, Mechanistically Grounded, and Empirically Falsifiable Theoretical Framework with Integrated p53-MDM2 Dynamics, Expanded Dynamic Stability Analysis, Global Sensitivity Analysis, Bayesian Inference, and Quantitative Risk Assessment for Autologous Restoration of Erythropoiesis in Severe Aplastic Anemia, Diamond-Blackfan Anemia, and Hereditary Bone Marrow Failure Syndromes
We present a rigorously upgraded and extensively detailed in silico theoretical framework for Spleno-Medullary Progenitor Cell Transplantation (SMPT), an autologous cellular intervention hypothesized to restore effective erythropoiesis in severe aplastic anemia (SAA), Diamond-Blackfan anemia (DBA), and a spectrum of hereditary bone marrow failure syndromes. The framework incorporates a dedicated fifth compartment modeling p53 activity with explicit biochemical kinetics derived from the p53-MDM2 negative feedback loop and ribosomal stress sensing (RPL5/RPL11). The five-dimensional deterministic/stochastic ordinary/stochastic differential equation (ODE/SDE) system is subjected to comprehensive analytical stability analysis, including derivation of the full Jacobian matrix, analytical equilibrium solutions, Lyapunov-based global stability proofs, bifurcation analysis with respect to engraftment efficiency, and phase-plane projections. Global sensitivity analysis (Sobol indices up to second-order, N=10^4 Saltelli samples across six key parameters: β, κ, η, δ, γ, λ) and time-dependent sensitivity heatmaps are presented. Bayesian inference, optimized via a steady-state algebraic surrogate for MCMC feasibility (4 chains, 2000 draws), yielded robust posterior estimates with strict convergence (R̂ ≤ 1.01, ESS >800). Monte-Carlo uncertainty quantification (N=5000 SDE trajectories) predicts robust restoration of normalized RBC counts to R(200)=209.37 under nominal SMPT conditions (β=0.35). A branching-process model estimates the probability of ex-vivo acquisition of a myeloid driver mutation at 3.0×10^{-6} per progenitor cell. Every central claim is formulated as a Popperian-falsifiable hypothesis, and all computational outputs are fully reproducible via the complete Python code provided in the Supplementary Information (with explicit random seeds, tolerance settings, and modular syndrome-specific parameter overrides). This work establishes a quantitative, evidence-anchored, and mechanistically explicit foundation for future experimental validation of niche-engineered autologous therapies across inherited and acquired bone marrow failure syndromes.
2026-04-10 | Spleno-Medullary Progenitor Cell Transplantation (SMPT): A Mechanistically Grounded, Empirically Falsifiable Theoretical Framework for Autologous Restoration of Erythropoiesis in Severe Aplastic Anemia and Diamond-Blackfan Anemia
We introduce a novel in silico conceptual framework for spleno-medullary progenitor cell transplantation (SMPT), positing it as a targeted autologous intervention designed to restore red blood cell (RBC) production in two severe bone marrow failure syndromes: aplastic anemia (SAA) and Diamond-Blackfan anemia (DBA). The core hypothesis of SMPT is the strategic exploitation of the spleen's known, albeit often latent, reservoir of stress-adapted erythroid progenitors. These progenitors would be harvested, robustly expanded ex-vivo, and subsequently re-infused into a specifically cytokine-primed bone marrow niche. Mechanistically, this approach is hypothesized to circumvent the T-cell-mediated autoimmune destruction of hematopoietic stem and progenitor cells (HSPCs) characteristic of SAA. Furthermore, in DBA, SMPT proposes a potential mitigation of the ribosomal biogenesis defects and subsequent p53-mediated erythroid apoptosis through an as-yet-uncharacterized niche-mediated compensatory mechanism, thereby addressing the fundamental defect while eliminating allogeneic transplantation risks.A four-compartment deterministic/stochastic ordinary/stochastic differential equation (ODE/SDE) model, rigorously parameterized from comprehensive peer-reviewed kinetic data and subjected to advanced computational analyses—including global sensitivity analysis (Sobol indices, \(N=10\,000\) Monte Carlo samples), Bayesian posterior inference, and Monte-Carlo uncertainty quantification (\(N=5000\) simulations)—predicts a restoration of normalized RBC counts from a near-zero baseline to \(R(200)\approx 247.72\) (arbitrary units, representing physiological levels) within 200 days post-intervention, under the stated model assumptions. Crucially, all mathematical derivations, parameter values, supporting Python code, and simulated outputs are entirely computationally reproducible. This manuscript rigorously establishes a mechanistically grounded and empirically falsifiable theoretical foundation for future experimental validation of niche-engineered autologous cellular therapies in challenging bone marrow failure syndromes. Each central claim is explicitly formulated as a testable hypothesis, strictly adhering to Popperian falsifiability criteria to facilitate robust scientific inquiry.
2026-04-10 | Umbilical cord blood transplantation in children with Diamond-Blackfan anemia.
Diamond-Blackfan anemia (DBA) is a rare inherited bone marrow failure syndrome characterized by macrocytic anemia and physical malformations. The only available curative treatment for patients with DBA is hematopoietic cell transplantation (HCT). Previous studies have included umbilical cord blood transplantation (UCBT) alongside other graft sources. We conducted a retrospective analysis of 41 pediatric patients with DBA who underwent related or unrelated UCBT between 1994 and 2023, using data from the Eurocord/EBMT registry. Twenty patients received related and 21 received unrelated single UCBT. Most patients received myeloablative conditioning and were transplanted after 1999. In related UCBT, median follow-up was 144.8 months, neutrophil engraftment at day +42 was 100% and 5-year overall survival (OS) was also 100%. In unrelated UCBT, median follow-up was 34 months, neutrophil engraftment at day +42 was 90%, and 5-year OS was 66%. The incidence of acute graft-versus-host disease (GvHD) was considerably higher among unrelated UCBT recipients. The incidence of chronic GvHD was similar between the two cohorts; however, extensive disease was more common after unrelated UCBT. UCBT from an HLA-identical sibling should be considered for DBA patients given the favorable short- and long-term outcomes. For the remaining patients, unrelated UCBT could be considered after individualized risk-benefit assessement.
2026-03-26 | Spleno-Medullary Progenitor Cell Transplantation (SMPT): A Mechanistically Grounded Theoretical Framework for Autologous Restoration of Erythropoiesis in Severe Aplastic Anemia and Diamond-Blackfan Anemia
We present a novel in silico conceptual framework for spleno-medullary progenitor cell transplantation (SMPT) as a targeted autologous intervention to restore red blood cell (RBC) production in severe aplastic anemia (SAA) and Diamond-Blackfan anemia (DBA). The approach hypothesizes exploitation of the spleen's latent reservoir of stress-adapted erythroid progenitors—harvested, ex-vivo expanded, and re-infused into a cytokine-primed marrow niche. This may circumvent autoimmune HSPC destruction in SAA and potentially mitigate ribosomal biogenesis defects in DBA through niche-mediated compensatory mechanisms, while eliminating allogeneic risks.A four-compartment deterministic/stochastic ODE/SDE model, parameterized from peer-reviewed kinetic data and subjected to global sensitivity analysis (Sobol indices), Bayesian posterior inference, and Monte-Carlo uncertainty quantification, predicts restoration of normalized RBC counts to R(200)≈247.72 (arbitrary units) from near-zero baseline under stated assumptions. All derivations, parameters, Python code, and simulation outputs are computationally reproducible. This manuscript provides a mechanistically grounded theoretical foundation for future experimental validation of niche-engineered autologous therapies in bone marrow failure syndromes.
small molecules
2026-07-23 | Ribosome biogenesis and selective translational control as oncogenic vulnerabilities in hematologic malignancies
The translation of the transcriptome into a functional proteome is not a passive readout of mRNA abundance but a primary regulatory layer that actively shapes the oncogenic landscape. In hematologic malignancies, convergent oncogenic signaling pathways, including MYC, PI3K/AKT/mTOR, and tyrosine kinase fusions, directly reprogram the translational apparatus, driving a qualitative shift toward the selective synthesis of pro-survival, proliferative, and stemness-associated proteins. This deregulated program is orchestrated through multiple interconnected axes: the accelerated biogenesis of ribosomes within the nucleolus, the assembly of the eIF4F initiation complex, the activation of stress-adaptive programs like the integrated stress response (ISR), and a sophisticated layer of epitranscriptomic, tRNA, and RNA-binding protein-mediated regulation. Hematologic cancers provide a uniquely informative framework for deconstructing these processes, illustrated by inherited ribosomopathies, such as Diamond-Blackfan anemia syndrome and Shwachman-Diamond syndrome, which resolve the paradox of how ribosomal insufficiency can evolutionarily transition into malignant transformation. Beyond pathogenesis, the translational machinery represents a rich landscape of actionable vulnerabilities. Pharmacological targeting of RNA Polymerase I, eIF4A, and the ISR has demonstrated selective antitumor activity and synergistic potential with established therapies, including BCL-2 inhibition. This review synthesizes mechanistic and clinical evidence to position the ribosome as an active regulatory node rather than a passive decoding machine. We further examine the challenges facing the field, including translational plasticity under therapeutic pressure, the lack of validated companion biomarkers, and the emerging role of translational control in modulating anti-tumor immunity. Ultimately, we argue that defining the disease-specific translational states of leukemia and lymphoma is essential for the next generation of precision oncology, moving beyond genomic landscapes toward a proteomic-centered understanding of malignancy.
2026-06-30 | Factors determining successful allogeneic hematopoietic stem cell transplantation in children with inherited bone marrow failure syndromes
Introduction. Inherited bone marrow failure syndromes (IBMFS) constitute a heterogeneous group of rare genetic disorders associated with impaired hematopoiesis, congenital anomalies, and a high risk of transformation to myelodysplastic syndrome and acute myeloid leukemia. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative treatment for IBMFS. Aim: to identify factors determining the efficacy of allo-HSCT in pediatric patients with IBMFS. Materials and methods. This study analyzed data from 61 patients with IBMFS who had undergone allo-HSCT between 2005 and 2025 at the R.M. Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantation. Results. The median follow-up was 24 months. The overall survival (OS) at 1, 3, and 5 years post-transplantation was 88%, 85%, and 81%, respectively. The lowest 5-year OS was observed in the Fanconi anemia (47%) and Diamond–Blackfan anemia (86%) groups, whereas in the patients with other IBMFS the 5-year OS reached 100% (p = 0.003). Factors associated with improved survival included age younger than 5 years at transplantation (100% vs. 68%; p = 0.009), the use of myeloablative conditioning regimens (100% vs. 64.5%; p = 0.002), the use of post-transplant cyclophosphamide (PTCy) for graft-versus-host disease (GVHD) prophylaxis (100% vs. 67%; p = 0.02), and successful engraftment (88% vs. 33%; p = 0.002). GVHD prophylaxis regimens without calcineurin inhibitors were associated with a lower incidence of grade II–IV acute GVHD (11% vs. 44%; p = 0.03) and a reduced need for switching immunosuppression (5% vs. 35%; p = 0.02). Donor type and degree of HLA matching did not significantly affect survival. Conclusion. Allo-HSCT is a highly effective treatment for children with IBMFS, providing a 5-year OS of 81%. The best outcomes are achieved with allo-HSCT performed at an early age (under 5 years), the use of myeloablative conditioning regimens (when not contraindicated), and with the addition of PTCy to GVHD prophylaxis. The lowest survival was observed in the patients with Fanconi anemia, highlighting the need for further refinement of treatment protocols for this patient group. PTCy-based GVHD prophylaxis regimens without calcineurin inhibitors reduce the incidence of acute GVHD and improve the tolerability of immunosuppression.
2026-06-30 | Recovery of erythropoiesis in Diamond–Blackfan anemia using eltrombopag in a cellular model: interim study results
Introduction. Diamond–Blackfan anemia (DBA) is a rare congenital bone marrow failure syndrome classified as a ribosomopathy and characterized by selective aplasia of the erythroid lineage. Despite advances in understanding its pathogenesis, treatment options are still limited, and a significant proportion of patients remain transfusion-dependent. Aim: to evaluate the effect of eltrombopag on the colony-forming potential of bone marrow erythroid progenitors in DBA patients in vitro. Materials and methods. The study included 10 patients with genetically confirmed DBA and 7 healthy donors. Bone marrow mononuclear cells were cultured in a methylcellulose medium supplemented with eltrombopag at concentrations of 13 and 26 μg/mL. Results. In vitro, the addition of eltrombopag to bone marrow cell cultures from the patients with DBA resulted in a significant increase in the number of erythroid colonies compared to control cultures without the drug. For early erythroid progenitors, a statistically significant increase in the number of colonies was observed. Conclusion. These interim results suggest that eltrombopag may be considered a potential stimulator of erythropoiesis in DBA and support the need for further research in larger cohorts in order to clarify the clinical significance of the observed effects.
2026-06-28 | Danazol in Contemporary Clinical Practice: A Comprehensive Review of Pharmacology, Therapeutic Applications, and Emerging Roles in Hematological Disorders
Danazol, a synthetic androgen-derived steroid with distinctive structural and pharmacological properties, has maintained clinical relevance for over four decades despite significant therapeutic advances in its primary indications. Originally developed for the management of endometriosis, this multifaceted compound has demonstrated remarkable versatility across diverse medical specialties, extending its utility to hereditary angioedema, immune thrombocytopenia, and various bone marrow failure syndromes. The compound's unique mechanism of action, encompassing anti-gonadotropic effects, direct steroidogenesis inhibition, immunomodulation, and telomerase activation, explains its efficacy across seemingly disparate pathological conditions. This comprehensive review examines danazol's pharmacological foundations, clinical applications, adverse effect profile, and emerging therapeutic roles, with particular emphasis on its resurgence in hematological practice. The pharmacokinetic properties of danazol, including its oral bioavailability, extensive tissue distribution, and hepatic metabolism, underpin its clinical utility while simultaneously necessitating careful monitoring for drug interactions and toxicity. Recent evidence supporting danazol's efficacy in corticosteroid-refractory immune thrombocytopenia, Diamond-Blackfan anemia, and telomere biology disorders has revitalized interest in this established agent, particularly in resource-constrained settings where novel biological therapies remain inaccessible. The compound's manageable adverse effect profile, cost-effectiveness, and oral administration render it an attractive therapeutic option for appropriately selected patients, though the interprofessional healthcare team must remain vigilant regarding potential hepatic, cardiovascular, and androgenic effects. This review synthesizes current evidence to provide clinicians with a comprehensive framework for the rational use of danazol in contemporary practice, emphasizing the importance of individualized therapy, vigilant monitoring, and collaborative care coordination.
2026-06-23 | Metadichol as a Coordinated Activator of Core Cellular Machinery Part II—From Inhibition to Activation: Metadichol Is the First Coordinated Activator of the 47-Gene 60S Ribosomal Protein Repertoire
Background. Metadichol® (Nano-Policosanol; Nanorx Inc.) is a nano-emulsion of food-derived very-long-chain primary alcohols (C26–C36) that acts as a Vitamin D Receptor (VDR) inverse agonist at picomolar to nanomolar concentrations. Prior peer-reviewed work has documented its regulation of all 49 nuclear receptors, all 7 sirtuins, Toll-like receptors, and the Yamanaka pluripotency factors. The 60S large ribosomal subunit—the catalytic engine of the ribosome housing the peptidyl-transferase centre—is encoded by 47 ribosomal protein genes (RPL/RPLP) that also perform extraribosomal roles in p53 surveillance, inflammatory mRNA silencing, and developmental patterning. Whether a single food-derived compound can coordinately regulate this entire repertoire has not been tested. Methods. Human PBMCs were isolated by Histopaque-1077 density-gradient centrifugation and treated for 24 h with Metadichol at 0.1 pg/mL, 1 pg/mL, 100 pg/mL, 1 ng/mL, and 100 ng/mL alongside untreated controls. Total RNA was extracted (TRIzol), reverse-transcribed (500 ng; PrimeScript), and all 47 large-subunit RPL/RPLP genes were quantified by SYBR-Green qRT-PCR (39 cycles; 60 °C annealing) using gene-specific validated primers. Relative expression was computed by the 2^−ΔΔCq method with GAPDH as reference; significance by one-way ANOVA with Dunnett's test. Results. All 47 large-subunit ribosomal protein genes were significantly up-regulated by Metadichol relative to untreated control, but in a strikingly coherent, non-monotonic (biphasic) manner. At the lowest dose (0.1 pg/mL) 44 of 47 genes were suppressed below control (mean 0.53-fold), whereas activation rose to a sharp maximum at 1 ng/mL—where 33 of 47 genes reached their individual peak (mean 2.27-fold)—before partial relaxation at 100 ng/mL. The largest single responses were RPL30 (5.43-fold), RPL24 (4.78-fold), RPL37 (4.31-fold), RPL38 (4.30-fold), RPL34 (4.17-fold), RPL18 (3.92-fold), RPL37A (3.83-fold), and RPL23A (3.80-fold). The p53-axis regulators RPL5, RPL11, and RPL26, the GAIT-complex protein RPL13A, the Hox-selective translator RPL38, and the P-stalk genes RPLP0/RPLP1/RPLP2 were all induced. Hierarchical clustering resolved a dominant "1 ng/mL-peaking" co-regulated module; inter-dose correlation analysis showed the 1 ng/mL and 100 pg/mL profiles were the most concordant (r ≈ 0.52) while the suppressive 0.1 pg/mL profile was weakly correlated with the activating doses (r ≈ 0.25), defining two regulatory regimes. A 47×47 gene–gene correlation matrix revealed broadly positive co-regulation, consistent with a single shared upstream driver rather than gene-by-gene noise. Conclusions. Metadichol produces a stoichiometrically balanced, dose-tuned activation of the entire 60S ribosomal protein gene set in primary human immune cells. To our knowledge this is the first agent shown to coordinately up-regulate the complete large-subunit repertoire, and it runs counter to the existing ribosome pharmacopeia, which is almost entirely inhibitory (mTOR inhibitors, RNA Pol I inhibitors). The uniform direction and tight gene–gene correlation distinguish this from the selective, imbalanced RPL changes that drive ribosomopathies (Diamond–Blackfan anemia, 5q- MDS, T-ALL), and instead resemble the coordinated ribosome-biogenesis program of pluripotent and regenerating cells. A notable RPL5↔RPL11 (5S RNP) asymmetry marks RPL5 as the single most dose-sensitive node. These findings position Metadichol as the first coordinated, balanced transcriptional activator of translational capacity—the directional mirror image, at the level of gene expression, of both ribosomopathy and ribosome-inhibitor drugs—with implications for ribosomopathy, iPSC reprogramming, immune function, and ageing biology.
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.
2026-07-09 | [Inherited bone marrow failure syndromes].
Diamond-Blackfan anemia (DBA) is a classic example of an inherited bone marrow failure syndrome in the category of erythrocyte diseases. DBA mainly occurs due to ribosome dysfunction. In the peripheral blood, reticulocytes are reduced, and in the bone marrow, only erythroid cells are markedly reduced. DBA primarily develops in infants and is often caused by heterozygous allele mutations in ribosomal protein genes. Activation of p53, translation dysfunction, inflammatory signals, and imbalance of hemoglobin/heme synthesis have been shown to contribute to impaired erythropoiesis and decreased red blood cell production. Patients with DBA are primarily treated with steroids; however, half of these patients eventually become unresponsive to long-term steroid treatment and become transfusion-dependent. Hematopoietic cell transplantation is currently the only curative treatment. Recent advances in gene therapy using lentiviral vectors have shown potential in promoting normal hematopoiesis in the treatment of RPS19-deficient DBA.
2026-07-01 | Case study report on diamond-blackfan anemia
Diamond-Blackfan anemia is a rare inherited bone marrow disorder that usually occurs during infancy. It causes reduced production of red blood cells, leading to severe anemia, poor feeding, pallor, lethargy, and poor growth.
2026-06-18 | Generation and characterization of human iPSC line SANi013-A from a Diamond-Blackfan anemia syndrome (DBAS) patient carrying a heterozygous RPS26 c.95-98 duplication variant.
Diamond-Blackfan Anemia Syndrome (DBAS) is a rare inherited bone marrow failure syndrome diagnosed in early childhood, marked by hypoplastic anemia, congenital anomalies, and increased cancer risk. Most cases involve loss-of-function mutations in ribosomal protein genes, disrupting ribosome biogenesis. We generated iPSC line SANi013-A from a patient with a de novo heterozygous RPS26 c.95-98 duplication. Proerythroblasts derived from peripheral blood were reprogrammed using a non-integrating Sendai virus method. The iPSC line SANi013-A displayed a normal karyotype, expressed pluripotency markers, and differentiated into all three germ layers. This line offers a valuable model for studying DBAS pathogenesis, especially erythropoietic defects.
2026-04-03 | Abstract 1168: Development of RT-dPCR-based functional release assays for the RPS19 gene therapy for Diamond-Blackfan anemia.
Abstract Diamond-Blackfan Anemia (DBA) is a congenital ribosomopathy primarily caused by heterozygous loss-of-function mutations in RPS19, a key component of the 40S ribosomal subunit. RPS19 haploinsufficiency disrupts ribosome biogenesis, triggers p53-dependent cellular stress, and impairs the survival of erythroid progenitor cells. Beyond severe anemia, DBA patients exhibit a slightly elevated risk of hematologic and solid malignancies, highlighting a direct link between ribosomal dysfunction and cancer predisposition. Currently, the only curative approach for DBA is allogeneic bone marrow transplantation which is associated with risk of graft failure and graft-versus-host disease. Gene addition using a third-generation self-inactivating lentiviral vector encoding RPS19 (SJEFS-S19 LV) offers a promising strategy to restore functional RPS19 expression in patient hematopoietic stem and progenitor cells (HSPCs) while maintaining genomic safety and avoiding immune toxicities. Preclinical studies demonstrate that SJEFS-S19 LV effectively corrects erythropoietic defects, restores pre-rRNA processing, and generates a polyclonal, genomically stable population of HSPCs. LVs predominantly integrate into open chromatin regions associated with active transcription. To ensure product quality and functional integrity, we developed a reverse transcription digital PCR (RT-dPCR)-based release assay designed to detect and quantify RPS19 transcript originating specifically from the integrated lentiviral vector following transduction. This approach partitions nucleic acid samples into thousands of micro-reactions, enabling absolute quantification with minimal amplification bias. For determining the RPS19 LV functionality, HEK293 RPS19-heterozygous knockout cells were transduced at varying multiplicities of infection (MOI), and total RNA was extracted for one-step RT-dPCR targeting the LV-derived codon-optimized RPS19 sequence. Increasing MOI correlated with higher normalized RPS19 transcript copies per ng genomic DNA, confirming successful vector integration and expression. This assay provides a robust, quantitative measure of functional gene expression, supporting critical quality attribute assessment of SJEFS-S19 LV. This functional assay concept is being translated into a critical release assay for the RPS19 Gene Therapy Drug Product in transduced CD34+ cells. Overall, this assay platform enables precise assessment of vector performance and provides a framework for translating LV gene therapy toward clinical applications in DBA patients, with potential implications for understanding how restoration of ribosomal protein function may impact oncogenic susceptibility. Citation Format: Neshat Masud, Sabina Ranjit, Nana Liu, Madhuri Kalathur, Senthil Bhoopalan, Catherine Willis. Development of RT-dPCR-based functional release assays for the RPS19 gene therapy for Diamond-Blackfan anemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1168.
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2026-04-01 | RPL34 deficiency establishes a Δ113p53-tunable model of DBA and enables in vivo reclassification of a missense variant
Although large human sequencing studies have proposed RPL34 as a candidate Diamond–Blackfan anemia (DBA) gene, direct in vivo functional evidence and variant-level validation have been lacking. Here, we functionally characterize loss of rpl34 in zebrafish, which recapitulates DBA hallmarks (severe anemia, developmental abnormalities) and activates p53/Δ113p53. In parallel, a precise orthologous knock-in of a reported human RPL34 missense allele (chr4:109546294:G>A) showed no hematopoietic defect in vivo , providing ACMG BS3-consistent functional evidence suggesting a benign impact in vivo ; however, definitive clinical classification will require corroborating human genetic and cellular evidence. Genetic attenuation of p53 or Δ113p53 reduced apoptosis and partially restored erythropoiesis and survival. Δ113p53 knockdown mitigated anemia in additional p53-dependent RP-deficiency models ( rpl18 , rpl17 , rps19 , rps14 ) but not in the p53-independent nop56 model, indicating a context-dependent mechanism. Together, these data establish RPL34 deficiency as a tractable in vivo model of DBA and identify Δ113p53 knockdown as a context-dependent modulator of p53-driven erythropoiesis.
2025-04-29 | Inflammatory pathways and the bone marrow microenvironment in inherited bone marrow failure syndromes.
Inherited bone marrow failure syndromes (IBMFS) are a diverse group of genetic disorders characterized by insufficient hematopoietic cell production due to blood stem cell dysfunction. The most common syndromes are Fanconi Anemia, Diamond-Blackfan Anemia, and Shwachman-Diamond Syndrome. These conditions share a theme of chronically producing pro-inflammatory cytokines such as TNF-α, IL-1β, IL-6, TGF-β, IFN-I, and IFN-γ. Each of these cytokines can impact the bone marrow microenvironment and drive the pathophysiology of IBMFS. This review aims to provide the latest progress in the field regarding the mechanistic underpinnings of inflammation in these IBMFS, as well as the effect of inflammation on the bone marrow microenvironment. A comprehensive understanding of the inflammation in IBMFS will open new avenues for intervention to restore bone marrow stability and improve patient prognosis. Future research must include targeting these mechanisms to develop novel therapies that can potentially mitigate the effects of chronic inflammation in IBMFS.
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.
2024-04-01 | Use of IV immunoglobulin to treat steroid resistant, immune checkpoint inhibitor induced pure red cell aplasia. A case report
Pure Red Cell Aplasia (PRCA) is a condition defined by depleted erythroid precursors on bone marrow biopsy, normocytic normochromic anaemia and reticulocytopenia.1 PRCA is most commonly idiopathically acquired, but it can be congenital, associated with infection or medications such as immune checkpoint inhibitors (ICIs). Nivolumab and ipilimumab are two novel ICIs that promote immune activation against tumour cells via T cell-mediated apoptosis. They are efficacious immunotherapies and are thus licensed for the treatment of many malignancies, including melanoma.2-4 Despite lacking the substantial side effect profile of older cytotoxic agents,3-5 ICIs can cause overactivation of the immune system, leading to immune-related adverse effects against non-cancerous cells.6-7 Immune mediated attack of erythroid precursors causes PRCA. Due to the rarity of PRCA, and the recent introduction of ICIs, few cases of ICI-related PRCA have been reported.8 ICI-induced haematologic toxicity can be fatal and prompt treatment is essential.7 High dose corticosteroids should be used first line, but treatment for steroid-refractory PRCA is challenging and little literature exists to guide therapy. Here we describe a case of immune-mediated PRCA, neutropenia and thrombocytopenia secondary to nivolumab and ipilimumab in a 38 year old woman. She had a history of BRAF V600-mutated melanoma which had been treated by wide local excision, however, five years after treatment she represented with local recurrence and distal metastases, for which she received nivolumab and ipilimumab. 97 days after starting this regime she presented with fatigue, nausea and exertional breathlessness. Blood tests found pancytopenia (Hb 75 g/L, previously 135 g/L, neutrophils 1.1 × 109/L, previously 2.6 × 109/L and platelets 66 × 109/L, previously 186 × 109/L) (Table 1). After 2 weeks of high dose corticosteroids treatment and wean, the neutrophils and platelets normalised but the low Hb and reticulocytopenia persisted. Further investigations were conducted, including bone marrow aspirate and trephine biopsy showed normal granulo- and megakaryopoesis but with absent erythroid islands (Fig. 1), confirmed PRCA. Second-line treatment options included cyclosporin and intravenous immunoglobulin. Due to the fear of melanoma relapse necessitating prompt restart of ICI, the faster acting IVIg was selected. A repeat haemoglobin 11 days later was 120 g/L with a reticulocyte count of 93 × 109/L. Nivolumab monotherapy was restarted 3 weeks after her IVIg without relapse of PRCA. 3 months after her last nivolumab treatment she remains in remission from PRCA and other immune cytopenias. Upon literature search and analysis, only five other described patients with ICI-induced PRCA failed to respond to steroids and were treated with IVIg.8,9 Whilst response rates to second-line ciclosporin are also high, the advantage of IVIg is the rapid response and single dose nature of the treatment. High dose corticosteroids should remain first line therapy for ICI-induced PRCA and we propose that IVIg be used as the treatment of choice for steroid-refractory disease and that ciclosporin is only started as a third-line. We also provide the first evidence that it is possible to re-challenge patients with ICI who go into remission following IVIg salvage.
2024-01-08 | Refractory Pure Red Blood Cell Aplasia Secondary to Major ABO-Incompatible Allogeneic Stem Cell Transplantation Successfully Treated With Daratumumab.
Pure red cell aplasia (PRCA) is a rare hematologic phenomenon that is usually associated with inherited genetic mutations such as in Diamond-Blackfan anemia. However, due to the emergence of allogenic stem cell transplantation in the treatment of various malignant and non-malignant disorders, the incidence of PRCA has increased. PRCA following hematopoietic stem cell transplant (HSCT) is more commonly seen in the setting of a major ABO-incompatible transplant. Treatment of allo-HSCT induced PRCA can be initially supportive as it takes time for the bone marrow to fully recover. However, prolonged and/or failure of the bone marrow to recover, significantly increases patient's risk of iron overload in the setting of frequent transfusions. Iron deposition can potentially lead to severe life-threatening multiorgan involvement which can be fatal. Therefore, earlier recognition and intervention with immunomodulators in patients who undergo frequent transfusions can be beneficial to mitigate this risk. Here, we present a case with severe transfusion-dependent PRCA following major ABO-incompatible allo-HSCT successfully treated with daratumumab.
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Drug Discovery Landscape
5 orphan drug designations for Diamond-Blackfan anemia.
5 orphan drug designations for Diamond-Blackfan anemia.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Dasatinib | small molecules | EMA | 2026-06-19 | — | Consorcio Centro De Investigacion Biomedica En Red |
Autologous CD34+ enriched cells transduced with a self-inactivating lentiviral vector containing the codon-optimized RPS19 gene | gene therapies | EMA | 2021-11-12 | — | Consorcio Centro de Investigación Biomédica en Red |
Autologous CD34+ cells transfected with a lentiviral vector containing codon optimised RPS19 gene | gene therapies | EMA | 2021-08-20 | — | Medicinal Product Lifecycle Management |
CD34+ cells that have been transduced in vitro with a lentiviral vector carrying a codon-optimized sequence for expressing the wild type RPS19 protein | gene therapies | FDA | 2020-10-21 | — | Apriligen, Inc. |
Interleukin-3 human (recombinant) | proteins | FDA | 1991-05-20 | — | Immunex Corporation |
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