RARE DISEASE
Sickle cell disease and related diseases
Sickle cell disease and related diseases
Sickle cell disease and related diseases
Drug discovery
111
drugs
With orphan designations
Overview
Sickle cell disease (SCD) is an inherited hemoglobinopathy characterized by abnormal, sickle-shaped red blood cells that cause vaso-occlusion, chronic hemolytic anemia, and multiorgan damage. Clinical manifestations include acute pain crises, stroke, infections, and progressive organ dysfunction. Management integrates disease-modifying therapies (e.g., hydroxyurea, gene therapies) and supportive care to reduce complications and improve quality of life [1][3][11].
Population
Affects ~100,000 Americans, predominantly non-Hispanic Black individuals (1 in 365 births) and Hispanic Americans (1 in 16,300 births) [2][17].
Global prevalence exceeds 7.7 million, with 80% of cases in sub-Saharan Africa [9][14]. Newborn incidence is rising, projected to reach 400,000 annual births by 2050 [14][15].
Burden
Reduces US life expectancy by >20 years; in low-resource settings, ≤90% mortality before adulthood [4][7][14].
Total mortality burden reached 376,000 deaths globally in 2021, 11× higher than cause-specific estimates [4][9].
Complications drive frequent hospitalizations, with high socioeconomic vulnerability in 67% of US cases [2][10].
Categories: rare genetic diseases, rare hematological diseases, rare transplant-related disorders
Research Papers
1,757 drug discovery papers about Sickle cell disease and related diseases, with 3 first-in-class and 59 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
1,757 drug discovery papers about Sickle cell disease and related diseases, with 3 first-in-class and 59 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
proteins
2026-09-26 | Extracellular Hemoglobin, Hypoxia, and Macrophage-Mediated Pulmonary Vascular Remodeling in Hemolytic Disease.
Pulmonary hypertension (PH) is a well-recognized complication of chronic hemolytic anemias such as sickle cell disease and thalassemia, yet the relative contributions of hypoxia and cell-free hemoglobin (Hb) to disease progression remain incompletely understood. Patients with hemolytic anemia experience a lifelong cycle of chronic and inter bitten hypoxia that compounds vascular injury driven by extracellular Hb and its degradation products, heme and iron. While the effects of hypoxia and Hb exposure have historically been studied in isolation, the combined impact of sustained, low-level plasma Hb together with chronic hypoxia-more representative of steady-state hemolysis-has been largely overlooked. A rat model incorporating chronic hypoxia with continuous low-dose Hb infusion via an implanted pump demonstrates that even modest plasma Hb concentrations (10-20 µM heme) exert an additive effect on hypoxia-induced PH. This effect is associated with increased adventitial macrophage accumulation, oxidative stress, and inflammation, driving more severe pulmonary vascular remodeling. Building on this model, therapeutic strategies targeting Hb-mediated vascular injury are evaluated, with particular focus on repeated-dose haptoglobin (Hp) therapy, given that Hp is often severely depleted in sickle cell disease. Restoring circulating Hp sequesters plasma Hb into a non-reactive, compartmentalized Hb-Hp complex, limiting NO scavenging and oxidative damage. These mechanistic findings are further linked to functional outcomes through studies of skeletal muscle microvascular oxygen tension and exercise capacity in Berkeley sickle cell disease mice. This review synthesizes findings across these studies to clarify the interplay between hypoxia, macrophage biology, and extracellular Hb in driving pulmonary vascular remodeling and to highlight emerging Hb-targeted therapeutic strategies for hemolysis-associated PH.
2026-08-14 | Augmenting hemopexin-mediated heme scavenging mitigates sepsis-induced acute kidney injury in humanized sickle cell mice.
Sickle cell disease (SCD) is characterized by chronic intravascular hemolysis and depletion of the heme scavenger hemopexin (HPX), generating a high-heme milieu that may increase susceptibility to inflammatory organ injury. Sepsis is a leading cause of acute kidney injury (AKI), yet the contribution of hemolysis-derived free heme to polymicrobial sepsis-associated AKI in SCD remains poorly defined. Using humanized SCD mice, we tested whether augmenting heme clearance via HPX mitigates septic AKI. Low-grade cecal ligation and puncture induced exaggerated systemic inflammation, elevated circulating heme and ferritin, and marked reductions in glomerular filtration rate (GFR) in sickling (hemoglobin SS [HbSS]) mice compared with nonsickling (HbAA) control mice. Septic SS mice also exhibited enhanced renal nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 inflammasome activation, increased oxidative stress, and tubular injury, consistent with heme-driven inflammatory and cytotoxic signaling. Acute administration of purified human HPX reduced circulating heme and ferritin, attenuated cytokine responses, and preserved GFR, indicating that restoration of heme buffering in SCD interrupts kidney injury pathways during septic stress. To achieve sustained heme control, we restored HPX expression using liver-directed delivery of adeno-associated virus serotype 8 (AAV8). AAV8-HPX restored hepatic HPX, reduced basal and sepsis-induced plasma heme levels, conferred protection against kidney dysfunction and tubular stress, and improved survival without evidence of hepatotoxicity. Collectively, these findings identify free heme as a central mediator linking hemolysis to sepsis-associated AKI in SCD, and establish that HPX augmentation via protein replacement or gene therapy is a mechanistically targeted, potentially translatable therapeutic strategy to mitigate heme-driven tissue injury and improve outcomes in SCD-associated sepsis.
2026-02-02 | Luspatercept ameliorates disease phenotype and complications in the Townes mouse model of sickle cell disease.
Preclinical data demonstrating that luspatercept mitigates vaso-occlusive and anemia-related complications in the Townes sickle cell model provide a strong rationale for its evaluation in SCD patients.
2025-12-09 | Thrombomodulin protects against acute vascular and multiorgan injury in sickle cell disease.
Vaso-occlusive episodes (VOEs) in the setting of hyperhemolysis can rapidly evolve into multiorgan failure in sickle cell disease (SCD). Although the mechanisms for rapid progression to multiorgan failure are unclear, a systemic vasculopathy with thrombotic microangiopathy-type features has been described. Reduced thrombomodulin (TM) function is implicated in some thrombotic microangiopathy syndromes. We observed a greater decline in platelet count and hemoglobin concentration and an increase in vascular injury biomarkers within 24 hours of admission for a VOE in 12 patients with SCD with multiorgan failure versus 12 patients without multiorgan failure. We observed decreased TM expression on the lung and kidney vasculature of 3 additional patients with SCD with multiorgan failure compared with a control patient without SCD. Transgenic SCD mice challenged with cell-free hemoglobin had reduced TM function, increased vascular injury biomarkers, and reduced renal cortical blood flow. Infusion of recombinant TM 2 or 24 hours after the challenge restored cortical blood flow and mitigated increases in vascular injury, complement activation, and tubular injury biomarkers, and protected against acute kidney and lung injury. We demonstrated that impaired TM function may be involved in the systemic vasculopathy of SCD-related multiorgan failure, and infusion of recombinant TM may restore vascular function and protect against acute organ damage.
2025-09-26 | Combined haptoglobin and hemopexin therapy for the treatment of cardiopulmonary dysfunction in sickle cell disease.
Hemolysis and the downstream consequences of cell-free hemoglobin (Hb) and heme contribute to the development of sickle cell disease pulmonary hypertension (SCD-PH). The plasma concentrations of Hb and heme scavenger proteins haptoglobin (Hp) and hemopexin (Hpx) in sickle cell patients are observed to be significantly lower than healthy donors. The unchecked exposure to Hb and heme contribute to vasculopathy and aberrant cardiac function. This is consistent with vascular remodeling co-localized within iron rich macrophages. Based on these observations in patients, we hypothesize that a joint Hb and heme scavenger approach, combining Hp + Hpx as a therapeutic will attenuate hemolysis driven SCD-PH progression in a SCD mouse model. To test the hypothesis, we utilized our validated Berk-SS mouse model of SCD-PH driven by a 10-week moderate hypoxia exposure and weekly subcutaneous administration of Hp + Hpx. At study termination, we analyzed changes in cardiopulmonary iron deposition, right ventricular and pulmonary functional parameters, and multi-omic indices associated with SCD-PH. Our data demonstrates that Hp+Hpx improves pulmonary vascular resistance and right ventricular function including stiffness, afterload, cardiac output, ventricular to vascular coupling ratio, pulmonary vascular resistance and medial hypertrophy. Histological evaluation of lung and right ventricular tissue demonstrates attenuation of cardiopulmonary pathology. Finally, a multi-omic analysis of whole lung and heart tissue demonstrates a rebalancing of proteins related to PH, iron, inflammation, and oxidative stress. This data provides strong pre-clinical evidence for the clinical study of combined Hb and heme scavenger proteins in the treatment of PH-associated SCD.
small molecules
2026-09-24 | Beyond Pain: A Pilot Study of Neurodegenerative and Mitochondrial Pathway Alterations in Sickle Cell Disease Using Platelet Proteomics.
Sickle cell disease (SCD) is a systemic disorder marked by chronic pain and neurocognitive deficits, yet the molecular drivers of these neurocognitive features remain poorly defined. Platelets, central to inflammation and vascular homeostasis, may reflect broad pathophysiologic processes in SCD. We performed high-resolution mass spectrometry on ultra-purified platelets from 16 adults with SCD and moderate to severe pain (self-reported ≥ 3/10 in the past year), identifying 4196 proteins, of which 1046 were significant (FDR < 0.05). Unsupervised clustering was used to stratify individuals into high- and low-pain phenotypes. Contrary to expectations, canonical pain pathways were not enriched. Instead, significant alterations were observed in neurodegeneration, mitochondrial metabolism, ATP regulation, mitophagy, and tRNA aminoacylation pathways between high- and low-pain phenotypes. High-pain individuals exhibited elevated levels of proteins involved in proteostasis and neurodegenerative disease processes, whereas low-pain individuals showed increased expression of proteins linked to mitochondrial integrity, neuroprotection, and reduced oxidative stress. Protein-protein interaction networks revealed tightly connected clusters within neurodegenerative and central nervous system-related pathways. Disease association analysis ranked neurodegenerative and mitochondrial pathways above traditional hematologic and nociceptive mechanisms. These findings suggest that platelet proteomics may serve as a peripheral window into PNS or CNS vulnerability and cognitive risk in SCD. The enrichment of tRNA aminoacylation and mitochondrial regulation pathways underscores the metabolic complexity of SCD and highlights novel targets for biomarker development and therapeutic intervention.
2026-09-16 | Prehospital management of pain associated with acute complications of Sickle Cell Disease: a preliminary nationwide cross-sectional study.
We aimed to describe the epidemiology of emergency medical services (EMS) encounters for sickle cell disease (SCD) complications, assess clinical practice patterns, and evaluate factors that may be associated with analgesia administration for SCD-related pain throughout the US. We completed a cross-sectional analysis using a nationwide sample of 9-1-1 advanced life support encounters during 2023 where the EMS clinician impression indicated complications of sickle cell disease. Outcomes of interest included pain scale measurements, pain management, and naloxone administration. Descriptive statistics were computed and stratified by key patient- and encounter-related factors. Among a total of 10,023 EMS encounters for SCD complications, 5.2% were pediatric, 48.6% were female, and 94.2% took place in urban settings. Median patient contact time was 22.2 min (IQR: 15.4-31.0). Pain scale measurements were documented in 73.0% of encounters and analgesia of any kind was administered in 13.5% of cases, including opioids in 11.7%. Naloxone administration was rare (<0.1%). Among patients whose pain scale was ≥7/10, encounters where patient contact lasted 20 min or greater had intravenous access established nearly five-times more often and received any analgesia or opioids roughly ten-times more often. In this large nationwide sample of EMS encounters for SCD complications, we found that administration of analgesia occurred more often during encounters with longer EMS-patient contact. However, low rates of pain control in all cases leaves room for improvement in EMS management of SCD-related pain, perhaps via intranasal analgesia.
2026-09-03 | Proximal tubulopathy in adult sickle cell disease: association of alpha-1 microglobulin.
Sickle cell nephropathy remains a major contributor to morbidity in adults with Sickle Cell Disease (SCD), yet proximal tubular injury remains insufficiently characterized, particularly in African settings. Alpha-1 Microglobulin (A1M), a low-molecular-weight protein, may serve as a sensitive biomarker of proximal tubular dysfunction. The authors conducted a multicentre observational cross-sectional study among 246 adults with stable SCD in Kinshasa, Democratic Republic of the Congo. Proximal tubulopathy was defined as A1M/Cr ≥ 20 mg/g. Measured Glomerular Filtration Rate (mGFR) was assessed by plasma iohexol clearance. Associations were evaluated using a pre-specified multivariable logistic regression model with multiple imputation for missing data. Proximal tubulopathy was present in 48% of participants. After adjustment, vaso-occlusive crises during the previous trimester (aOR = 1.96, 95% CI 1.14-3.35), leg ulcers (aOR = 2.11, 95% CI 1.16-3.82), and albuminuria (log-transformed UACR; aOR = 1.53, 95% CI 1.24-1.88) were independently associated with elevated A1M/Cr. Hydroxyurea use was associated with lower odds of proximal tubulopathy (aOR = 0.54, 95% CI 0.31-0.95). In a model adjusted for albuminuria, no independent associations were observed for markers of hemolysis or measured GFR, suggesting that the effects of these factors on tubular injury may be mediated through glomerular injury or are closely intertwined with it. Sensitivity analyses excluding albuminuria from the model (Tables S2-S5) did show associations with leg ulcer, recent VOC, and systolic blood pressure. Proximal tubular dysfunction is frequent among adults with SCD in this high-burden African setting and was independently associated with markers of disease severity and renal involvement.
2026-08-27 | Colchicine Protects Against Sickle Cell Related Cardiomyopathy: Evidence of the Novel Role of Inflammaging.
Sickle cell disease (SCD) is a globally distributed hereditary red cell disorder with still high mortality. Growing evidence indicates that sickle cell related cardiovascular disease contributes to the early death of adults with SCD. Here, we show that humanized SCD mice developed an age-dependent cardiomyopathy characterized by (i) increased circulating Th17 lymphocytes, Th17 heart infiltration associated with increased plasma IL-17; (ii) collagen deposition and activation of both platelet derived growth factor-B (PDGF-B) and transforming growth factor-β1 (TGF-β1) canonical pathways; (iii) overactivation of heart NF-κB associated with up-regulation of NLRP3 and of inflammatory vasculopathy markers. We then used colchicine (CLC) that acts as anti-inflammatory drug with immunomodulatory effects. In humanized SCD mice, we demonstrated the protective role of low-dose CLC treatment against chronic inflammation and preserving myocardial performance. Of note, we found CLC also attenuating sickle cell related lung damage, suggesting a multiorgan effect of CLC in SCD mice. Our data generate the rationale to further explore CLC as new therapeutic tool to treat early stages of sickle cell cardiomyopathy.
2026-08-06 | An ancient mitochondrial program tunes translation to haem availability.
Anaemia is a major global health burden that affects one-quarter of the human population and annually accounts for over 50 million years of healthy life lost1. It arises from nutritional iron deficiency, hereditary disorders (including thalassaemia and sickle cell disease) and malaria, and is characterized by haemoglobin imbalances2. Haem-the active component of haemoglobin-is both essential and potentially toxic, which necessitates tight control of levels. However, the molecular circuitry that monitors haem levels remains obscure. The cytosolic eIF2α kinase HRI counteracts anaemia amid iron deficiency or thalassaemia3,4 by acting as a gatekeeper of translation during erythroid differentiation, which has been attributed to its haem-binding ability5. Here we uncover that haem scarcity is sensed inside mitochondria through an OMA1-DELE1 axis. Mechanistically, haem deficiency triggers OMA1-dependent mitochondrial release of DELE1. In the cytosol, DELE1 releases inhibitory haem from HRI, which enables modifications in a crucial disordered segment of the kinase. We demonstrate that this sensor-actuator operates across human tissues, including erythroid progenitors, and is evolutionarily conserved down to bloodless invertebrates, thus predating the emergence of haemoglobin-based oxygen transport. Notably, pharmacological manipulation of this system enhances fetal globin expression-a central therapeutic objective in haemoglobinopathies. Together, these results reveal a primordial sentinel system that safeguards against haem-related toxicity from the single-cell to the organismic scale.
gene therapies
2026-09-25 | Intracranial Arteriopathy and Ischemic Brain Injury in Adults With Sickle Cell Disease.
Cerebrovascular injury is a complication of sickle cell disease (SCD), but the spectrum of MRI/MRA abnormalities in adults remains incompletely characterized. We described imaging abnormalities in a consecutive adult SCD clinic cohort undergoing MRI/MRA and examined clinical risk factors and intracranial arteriopathy features associated with parenchymal abnormalities. We retrospectively studied 527 consecutive adults with confirmed SCD who underwent brain MRI/MRA as part of routine follow-up at a tertiary SCD clinic, not restricted to patients with a history of stroke or TIA. Parenchymal outcomes included cortical, lacunar, watershed, and large-vessel territorial infarcts, Fazekas score >1, and global cortical atrophy. For each ischemic or atrophy-related outcome, Model A examined associations with predefined clinical and laboratory factors. Model B added steno-occlusive arteriopathy (SOA) and dilative intracranial arteriopathy (DIA) to evaluate whether vascular imaging features were associated with parenchymal abnormalities beyond clinical factors alone. Mean age was 33.0 ± 12.6 years; 55.6% were female. Ischemic abnormalities included cortical infarcts (13.1%), lacunar infarcts (9.7%), watershed infarcts (5.3%), and large-vessel territorial infarcts (3.4%). SOA was present in 9.3% and was associated with Fazekas score >1, lacunar infarcts, and global cortical atrophy in multivariable models. In targeted analyses, SOA was also associated with watershed and large-vessel territorial infarcts. In a consecutive adult SCD cohort undergoing routine MRI/MRA, ischemic and atrophy-related abnormalities were frequent and heterogeneous overall. SOA, but not DIA, was associated with several parenchymal injury patterns, supporting the potential role of intracranial vascular imaging in refining cerebrovascular phenotyping in adults with SCD.
2026-09-24 | Systemic delivery of phagocytosis-shielded retroviral vectors enables in vivo HSC gene therapy for sickle cell disease.
Ex vivo hematopoietic stem cell (HSC) gene therapy is effective for non-malignant blood disorders including sickle cell disease (SCD), but requires hospitalization, ex vivo cell manipulation, and conditioning. Direct in vivo gene delivery could remove these barriers and widen access. Here, we explore phagocytosis-shielded lentiviral and alpha-retroviral vectors pseudotyped with the baboon endogenous retrovirus glycoprotein variant BaEVRLess for in vivo HSC gene transfer. Vector injection into mobilized humanized mice yielded up to 8.8% gene marking in hCD45+ cells, which chemoselection enriched to 70% of hCD45+ cells and 54% of HSCs. Barcode analysis showed polyclonal reconstitution in over 90% of mice, which remained stable in secondary recipients. For SCD, we targeted BCL11A and ZNF410 selectively in erythroid cells using miRNA-embedded shRNAs to derepress gamma-globin, reaching therapeutically relevant levels of 61.5% of beta-like globins. In summary, BaEVRLess-pseudotyped lentiviral vectors enable clinically relevant in vivo gene transfer and fetal globin induction for SCD.
2026-09-19 | Development of CRISPR_SCD001, an Autologous Hematopoietic Stem Cell Gene Therapy for Sickle Cell Disease after CRISPR-Cas9 Mediated Correction.
We developed CRISPR_SCD001, an autologous cellular therapy in which the pathogenic HBB sickle allele is corrected by CRISPR-Cas9-mediated homology-directed repair using a single-stranded oligodeoxyribonucleotide as DNA donor template. The Drug Product (DP) from Plerixafor-mobilized peripheral-blood CD34+ cells from sickle and healthy donors were used for: 1) pharmacodynamic assessments to interrogate therapeutic potential; 2) evaluation of genotoxicity; and 3) in vivo characterization by a non-GLP toxicology study in NBSGW mice. Large-scale DP lots yielded 89 ± 5 % CD34+ purity with 84 ± 6 % viability. Mean gene correction at HBB was 22 ± 4 % of alleles, with 51 ± 6 % of allelic disruption. Edited erythroid cultures produced 39 ± 5 % adult hemoglobin and 40 ± 6 % fetal hemoglobin, reducing sickle hemoglobin from 89% to 22 ± 6 %. In NBSGW mice, CRISPR_SCD001 engrafted robustly (59 ± 25%), maintained editing frequencies comparable to injected cells (∼20% gene correction), showed polyclonal distribution of the edited cells, and no noteworthy treatment-related toxicity or pathologic evident were found by a blinded histopathology assessment. Our protocol generates a clinical-grade, cryopreserved CD34+ cell product that corrects the sickle mutation, restores anti-sickling hemoglobins, and meets pre-clinical safety criteria, establishing a reproducible manufacturing process suitable for clinical translation. These data support initiation of a first-in-human phase I trial of CRISPR_SCD001 for sickle patients presenting with severe pathology.
2026-09-19 | Gene therapy for hereditary hematological disorders: From clinical breakthroughs to future horizons.
Hereditary hematological disorders, including sickle cell disease, β-thalassemia, and hemophilia, are severe monogenic diseases that impose substantial morbidity and lifelong treatment burdens. Conventional therapies are largely supportive and rarely curative, whereas gene therapy is increasingly transforming the therapeutic landscape by addressing the underlying genetic defects. This review summarizes the major gene therapy strategies currently being developed for hereditary hematological disorders, with a particular focus on gene addition, gene editing, and gene silencing, as well as ex vivo and in vivo delivery platforms. We highlight recent clinical breakthroughs, including approved products for hemoglobinopathies and hemophilia, and discuss emerging approaches such as base editing, prime editing, epigenetic modulation, and lipid nanoparticle-mediated delivery. In addition, we examine the major challenges that continue to limit broader clinical adoption, including immune responses, off-target effects, conditioning-related toxicity, manufacturing complexity, high cost, and limited accessibility. Finally, we outline future directions that may accelerate clinical translation, including improved editing precision, next-generation vector engineering, artificial intelligence-assisted design, scalable manufacturing, and more equitable access to treatment. Together, these advances suggest that gene therapy is steadily moving from experimental innovation toward durable, potentially curative treatment for hereditary hematological disorders.
2026-09-06 | Kenya Sickle Cell Disease Public Health Literacy & Expert Insights Dataset (De-Identified FGDs, KIIs & Surveys)
This dataset contains de-identified qualitative and survey data collected to understand public health literacy, care experiences, and expert perspectives on sickle cell disease (SCD) in Kenya. The collection includes transcripts from Focus Group Discussions (FGDs) with people living with SCD and caregivers, Key Informant Interviews (KIIs) with Ministry of Health officials, healthcare providers, community representatives, and community health promoters (CHPs), as well as technical expert discussions and structured survey responses. The dataset captures themes related to SCD awareness, diagnosis and treatment pathways, access to care, psychosocial challenges, health information needs, health system barriers, and opportunities for improving community-based support and public health communication. All personal identifiers have been removed to protect participant confidentiality. This resource is intended to support research in public health, health communication, digital health, implementation science, and AI-enabled health systems, and provides contextual insights for the development of culturally appropriate interventions and evidence-based decision support tools for sickle cell disease in low-resource settings.
cell therapies
2026-08-23 | Prevalence of Alloimmunization Among Patients With Transfusion-Dependent Thalassemia and Sickle Cell Disease in Salmaniya Medical Complex, Bahrain.
Background Red blood cell (RBC) alloimmunization is a significant complication among patients with transfusion-dependent thalassemia and sickle cell disease (SCD), potentially leading to difficulties in crossmatching, delayed hemolytic transfusion reactions, and hyperhemolysis. In Bahrain, the prevalence of RBC alloimmunization among patients with hemoglobinopathies had not been previously reported. Objective To determine the prevalence of RBC alloimmunization among patients with transfusion-dependent thalassemia and SCD in Bahrain and to compare findings with published regional and international data. Methods A retrospective, cross-sectional study was conducted at Salmaniya Medical Complex (SMC), Bahrain. A total of 311 transfusion-dependent patients, 203 with SCD and 108 with thalassemia, registered between 2016 and 2025 were included. Clinical and laboratory data were extracted from electronic medical records. Patients with a positive indirect antiglobulin test (IAT) showing a consistent reaction strength of 2+ or greater were considered alloimmunized. Descriptive statistics were used to analyze demographic variables and determine the prevalence of alloimmunization. A chi-square test was used to compare alloimmunization rates between the SCD and thalassemia groups. The rates observed in this study were also compared with those reported in other countries using chi-square analysis. A p-value < 0.05 was considered statistically significant. Results The overall prevalence of RBC alloimmunization was 14.8%. Alloimmunization was significantly more prevalent among patients with SCD, with 41 out of 203 (20.2%) testing positive, compared to only 5 out of 108 (4.6%) patients with thalassemia (p < 0.001). Among the 46 alloimmunized patients, 58.7% were male, and 41.3% were female, reflecting the sex distribution of the study population. Blood group O was the most common (54.3%), and 95.5% of patients were Rh-positive. Conclusion The alloimmunization rates observed in this study are consistent with the rates reported in other Middle Eastern countries. Despite extended phenotypic crossmatching, patients with SCD had a significantly higher alloimmunization rate than patients with thalassemia, likely due to disease-related immune activation and differences in transfusion protocols. Adoption of molecular RBC genotyping and comprehensive antibody identification for all alloimmunized patients is recommended to improve transfusion safety in this population.
2026-08-01 | Mixed Myeloid Chimerism and Hemolytic Markers After Nonmyeloablative HCT for Sickle Cell Disease
Sickle cell disease (SCD) is a hemolytic anemia characterized by both intravascular and extravascular hemolysis. Allogeneic hematopoietic cell transplantation (allo-HCT) can be curative in SCD, including in the setting of mixed donor myeloid chimerism. Despite resolution of sickle-related disease complications and chronic anemia following allo-HCT, laboratory evidence of hemolysis may persist. The relationship between mixed myeloid chimerism and residual hemolysis remains incompletely defined and may have implications for newer genetic therapies where a portion of host hematopoietic stem cells remain uncorrected. We evaluated the association between donor myeloid chimerism and hemolytic indices—absolute reticulocyte count (ARC), lactate dehydrogenase (LDH), total bilirubin, and aspartate aminotransferase (AST)—in 88 adult patients with SCD following nonmyeloablative matched-related donor allo-HCT ( ClinicalTrials.gov ID: NCT00061568, NCT02105766). Seventy-three recipients were evaluable at a median follow-up of 5.74 years (range, 1.5-16.97), including 35 (46%) with mixed myeloid chimerism (5-95%). Hemolytic indices inversely correlated with donor myeloid chimerism in the mixed chimerism cohort, reaching statistical significance for all markers except LDH. Although all indices improved compared with pre-HCT values, patients with lower donor chimerism demonstrated higher residual hemolysis, with ARC significantly elevated in the ‘Mixed Low’ (20–50%) compared with ‘Mixed High’ (51–95%) cohort. ARC and LDH remained significantly lower in the ‘Mixed Low’ cohort compared to those with graft failure. Our findings demonstrate a negative correlation between donor myeloid chimerism and residual hemolysis following nonmyeloablative allo-HCT, supporting biologically relevant thresholds of corrected hematopoiesis that may help inform gene therapy approaches in SCD.
2026-07-27 | Evaluating the design and implementation challenges of the Centers for Medicare & Medicaid Services' Cell and Gene Therapy Access Model.
Cell and gene therapies (CGTs) offer potentially curative treatments for conditions like sickle cell disease but pose major affordability and access challenges for Medicaid mainly due to multimillion-dollar upfront prices. In response, the Centers for Medicare & Medicaid Services (CMS) introduced the CGT Access Model, a purchasing approach that leverages the Medicaid Drug Rebate Program to implement multistate, outcome-based agreements for CGTs. Through the Model, CMS negotiates core terms with manufacturers, states adopt these terms through rebate agreements, and CMS coordinates data collection and evaluation. The initiative aims to expand access, improve clinical outcomes, and generate long-term cost savings by aligning payment with demonstrated therapeutic benefit. However, critical uncertainties remain, including outcome-based agreement design, access policy standards, moral hazard risks, fertility-related barriers, out-of-state care challenges, and challenges with data collection. Although imperfect, the CGT Access Model marks an important step toward integrating sustainable financing of high-cost, transformative therapies into public insurance programs.
2026-07-23 | Transplant versus no transplant outcome in adolescents and adults with sickle cell disease eligible for allogeneic hematopoietic stem cell transplantation.
Hematopoietic stem cell transplantation (HSCT) remains the only curative option for sickle cell disease (SCD), but its use in adolescents and adults is limited by toxicity concerns. We evaluated the risk-benefit profile of HSCT in this population through a comparative analysis of transplant versus nontransplant strategies. HSCT was analyzed as a time-dependent variable in consecutive adolescents and adults with an indication for transplantation who were referred for HSCT counseling. At the last follow-up, patients had either undergone HSCT or not. HSCT procedures involved matched related donor (MRD) transplants after myeloablative or non-myeloablative conditioning, and haploidentical transplants after reduced-intensity conditioning. The primary endpoints were overall survival (OS) and composite event-free survival (cEFS), calculated from the initial consultation. Events included death, grade III-IV acute or moderate-to-severe chronic graft-versus-host disease (GVHD), graft rejection, overt stroke, third hospitalized painful crises within two years, acute chest syndrome (ACS), delayed hemolytic transfusion reaction, or initiation of new SCD modifying therapy. Ninety-four patients were included (median follow-up: 2.9 years), of whom 58 underwent HSCT. The 2-year OS was 98% with HSCT versus (vs.) 97% without HSCT (P = 0.55). cEFS was significantly higher post-transplant (72% vs. 28%, P < 0.0001), with marked reduction in painful crises and ACS. Among patients who underwent transplantation, the 2-year rejection-free survival from the time of transplant was 91% for MRD and 82% for haploidentical HSCT (P = 0.40). HSCT substantially improves cEFS without excess short-term mortality, supporting its broader use in adolescents and adults with SCD, particularly when an MRD is available.
2026-07-16 | Design, rationale, and baseline patient characteristics for the Sickle Cell Disease and CardiovAscular Risk-Red cell Exchange (SCD-CARRE) trial.
Despite wide utilization of automated red blood cell exchange (RBCX) transfusion in adult patients with sickle cell disease (SCD), no consensus or quality efficacy data exist on its use. The Sickle Cell Disease and CardiovAscular Risk- Red cell Exchange (SCD-CARRE) trial tests the hypothesis that an automated chronic RBCX transfusion strategy reduces acute health care encounters and death while improving quality of life and end-organ function (cardiac, pulmonary and renal) in participants with SCD that are at high risk of death. Adult patients with SCD with elevated tricuspid regurgitant jet velocity (TRV) and/or chronic kidney disease were considered to be at high risk of death and were randomly assigned to RBCX plus standard of care vs standard of care alone. Participants assigned to RBCX received 12 months of exchange transfusions to maintain target pretransfusion hemoglobin S% < 30%, post-transfusion hemoglobin S% < 20%, and post-transfusion hemoglobin concentration ≥10 g/dL. All study participants were managed according to NHLBI/ASH/ATS Expert Panel guidelines. The primary endpoint was the number of SCD acute health care encounters or death over 13 months. Secondary endpoints included measures of cardiovascular and renal function, exercise capacity, patient reported outcomes (all collected at baseline, and months 4, 8, and 12), and transfusion-related adverse events (collected monthly). Between 2020 and 2025, the SCD-CARRE trial randomized 173 participants at 23 sites across 3 countries. Enrolled participants had mean (SD) age of 45.8 (11.8) years and 54% were female. At baseline, participants had average TRV of 2.8 (0.5) m/s such that 45.9% had a TRV between 2.5 to 2.9 m/sec and 28.1% had a TRV ≥ 3.0 m/sec. The median (Q1, Q3) eGFR in this cohort was 60 (36, 110) mL/min/1.73 m2. The median (Q1, Q3) 6-minute walk test distance was 375 meters (309, 439), the median daily steps were 3,728 (2,187, 5,821), and participants experienced a median (Q1, Q3) of 2 (1, 5) pain episodes in the year prior to randomization. The trial results are pending. The SCD-CARRE trial successfully enrolled a cohort of n = 173 adults with SCD. This study highlights a rationale to evaluate the effect of automated chronic RBCX transfusion strategy plus standard of care as compared to standard of care alone in SCD patients at high risk of death with a focus on patient centered outcomes, preservation of cardiovascular function, end-organ complications and death. ClinicalTrials.gov, Identifier: NCT04084080, https://clinicaltrials.gov/study/NCT04084080.
other
2026-06-01 | Adaptive Immune Remodeling in Sickle Cell Disease: Linking Hemolysis-Driven Inflammation to Immune Dysfunction.
Sickle cell disease (SCD) is increasingly acknowledged not only as a hemoglobinopathy but also as a disorder of immune remodeling driven by persistent hemolysis and chronic inflammation. In this perspective review, we propose a mechanistic scaffold in which hemolysis-associated damage-associated molecular patterns (DAMPs) initiate sustained innate immune activation that reshapes bone marrow niche, i.e., alter hematopoietic stem and progenitor cell fate, alters lymphopoiesis, and progressively remodels adaptive immunity. We discuss emerging evidence linking chronic inflammatory signaling to T-cell activation, altered helper T-cell polarization, impaired germinal center dynamics, and depletion of memory B-cell compartments. We further highlight age-dependent immune remodeling across pediatric and adult SCD populations and discuss how these alterations may contribute to impaired vaccine response, increased susceptibility to infection, and transfusion-related alloimmunization. By integrating insights from hematopoiesis, inflammation, and adaptive immunity, this perspective reframes SCD-associated hemolysis and immune dysfunction as a central component of disease pathophysiology and identifies potential directions for future immunomodulatory and vaccine-focused therapeutic strategies..
2026-01-03 | Anti-IL-18 immunotherapy decreases inflammatory and vaso-occlusive responses in mice with sickle cell disease.
Sickle cell disease (SCD) is characterized by inflammatory and vaso-occlusive processes that drive acute crises and progressive organ damage. Interleukin-18 (IL-18), elevated in patients with SCD and mouse models, contributes to these pathological mechanisms. We evaluated the effects of acute and prolonged IL-18 blockade using the SK113AE-4 monoclonal antibody in Townes and Berkeley SCD mice. Acute IL-18 neutralization reduced tumor necrosis factor-alpha (TNF-α)-induced microvascular leukocyte recruitment and prevented hypoperfusion, indicating that modulation of inflammatory signaling improves physiological responses in SCD. Prolonged anti-IL-18 immunotherapy for 6 weeks decreased circulating TNF-α and IL-10 and reduced hepatic macrophage infiltration, but did not prevent liver fibrosis, iron deposition, or alter biochemical markers of hemolysis or hepatic/renal injury. As such, IL-18 blockade attenuates vascular inflammation and vaso-occlusive-like events but may be insufficient to prevent SCD-related liver injury under the conditions tested. In contrast, in our previous study, anti-IL-1β immunotherapy provided added liver protection, highlighting potentially divergent cytokine pathways in SCD. Collectively, these results support IL-18 as a therapeutic target to reduce vascular inflammation and vaso-occlusive processes, and suggest that combined inflammasome cytokine-targeted or multiapproach strategies may be required to prevent organ damage in SCD.
2025-12-03 | Managing acute myeloid leukemia in the context of sickle cell anemia and suspected Fanconi anemia in Tanzania: a case report.
The transformation of Fanconi anemia into a hematological malignancy is consistent with the natural history of the disease. Few cases have been reported on acute myeloid leukemia, and even fewer cases involving coexistence with sickle cell anemia. Acute myeloid leukemia development is postulated to follow a multihit hypothesis where preleukaemic cells progress into leukemia through a second promotional mutation. Fever is a predominant clinical presentation, with blasts usually observed on peripheral blood smear and the immunophenotype confirmed with flow cytometry. In this case report from Tanzania, we present a case of acute myeloid leukemia with a failed induction in a patient with Sickle cell anemia and suspected Fanconi anemia. A 6-year-old Haya boy from northern Tanzania presented to Muhimbili National Hospital with a congenital malformation of the left hand, short stature, and multiple café-au-lait spots distributed over the trunk, face, and limbs. He had experienced recurrent fever for 8 months, accompanied by headache, weight loss, and abdominal distension. Laboratory evaluation confirmed acute myeloid leukemia and sickle cell anemia with clinically suspicious features of Fanconi anemia. The patient was initiated on institutional treatment for acute myeloid leukemia. He had a failed induction and subsequently transitioned to home-based palliative care after prognostic counseling with the family. Thereafter, he had several admissions, mostly for blood product support, and eventually died 7 months post-discharge. The onset of acute myeloid leukemia in this case could be attributed to a malignant transformation from an underlying cancer predisposition syndrome. Our particular focus was on the leukemia treatment response where we observed a failed induction, prompting the need for alternative treatment approaches in this category of patients with acute myeloid leukemia in order to realize better treatment outcomes.
2025-05-15 | Rpl13a snoRNAs U34 and U35a: New Targets for Sickle Cell Disease Complications.
In sickle cell disease (SCD), erythrocyte reactive oxygen species (ROS) production and oxidative stress play a critical role in vaso-occlusion, a hallmark of SCD. Small noncoding nucleolar RNAs (snoRNAs) of the Rpl13a locus have been described as regulators of ROS levels. However, whether Rpl13a snoRNAs are present in sickle red blood cells (RBCs) and regulate ROS levels and whether they contribute to SCD pathophysiology remain unknown. To determine whether sickle RBC ROS levels are associated with Rpl13a snoRNA levels and identify the mechanism by which they regulate ROS and snoRNAs' effects on SCD hemodynamics, we used human RBCs, Rpl13a snoRNA knockout sickle mice, K562 U32a, U33, U34, U35a, and the control U25 knockout mutants generated by CRISPR-Cas9 (Clustered Regularly Interspaced Short Palindromic Repeats/Cas9 protein)-targeted genome editing, and genetic targeting with antisense oligonucleotides. Excessive ROS production in sickle RBCs of patients with SCD is associated with high Rpl13a snoRNAs U32a, U33, U34, and U35a levels. U32a, U34, and U35a regulate ROS and hydrogen peroxide levels in sickle erythroid populations by modulating peroxidase activity. This was due to U32a- and U34-guided 2'-O-methylation on Prdx2 (peroxiredoxin 2) messenger RNA, a modification conveyed by fibrillarin during erythropoiesis, subsequently reducing Prdx2 expression and activity. The snoRNA U35a impaired Prdx2 expression/activity but independently of Prdx2 messenger RNA 2'-O-methylation. Excess sickle RBC ROS increased in turn Rpl13a snoRNAs levels. In vivo targeting combinations of U34+U35a and U32a+U34+U35a in sickle mice with antisense oligonucleotide blunted RBC ROS generation, improved erythropoiesis and anemia, alleviated leukocytosis and endothelial damage, diminished cell adhesion in inflamed vessels and vaso-occlusion, restored blood flow, and reduced animal mortality. Rpl13a snoRNAs U34 and U35a specifically increase ROS levels, which, in turn, regulate snoRNA expression, in sickle erythroid cells, modulating Prdx2 expression/activity, subsequently impairing hemodynamics. Targeted U34+U35a with antisense oligonucleotide may represent a novel and safe therapy to ameliorate erythropoiesis and downstream events in SCD.
2025-05-04 | Serotype specific pneumococcal vaccine effectiveness in children with sickle cell disease: A two-decade analysis.
Sickle cell disease (SCD) is the most common genetic hematologic disease globally and children with SCD are at increased risk for pneumococcal disease. We utilized data from population-based enhanced surveillance for invasive pneumococcal disease (IPD) in children <18 years of age in Massachusetts from 2002 to 2020. We calculated incidence rates (IR) among children with SCD using bootstrapping resampling and incidence rate ratios (IRR) for pre- and post-PCV13 periods. Vaccine effectiveness (VE) was calculated as 100*(1-IRR), and PCV13 vaccine failure probability was predicted using a random forest model. Children with SCD had higher IR during both pre-/post-PCV13 periods compared with otherwise healthy children 240.0/100,000 versus 4.6/100,000 in pre-PCV13 period (2002-2009); 172.7/100,000 versus 1.9/100,000 in post-PCV13 period (2011-2020), respectively. After widespread use of PCV7 for a decade, a modest reduction of 28.1 % (95% CI 25.9-37.2%) in the incidence of overall IPD during the post-PCV13 period was observed in children with SCD, whereas a more substantial 59.5% (96% CI 57.8-61.4%) reduction was observed in otherwise healthy children. There was a 60.8% (95% CI 55.2%-NA) reduction in the incidence of VST13 IPD in children with SCD and an 83.0% (95% CI 80.67-85.63%) reduction in children without underlying health condition. Overall, 61.1% of the remaining IPD among children with SCD were due to non-PCV13 serotypes (8, 10A, 15A,15B, 22F, 23B), many of which are included in expanded valency vaccines. Children with SCD continue to have higher rates of IPD compared with otherwise healthy children despite vaccination. Majority of the remaining disease is due to serotypes not included in vaccine formulations that have been used for the last two decades. Our study highlights the potential value of expanded valency vaccines and importance of risk-based vaccination strategies tailored for this vulnerable population.
proteins
2026-09-26 | Extracellular Hemoglobin, Hypoxia, and Macrophage-Mediated Pulmonary Vascular Remodeling in Hemolytic Disease.
Pulmonary hypertension (PH) is a well-recognized complication of chronic hemolytic anemias such as sickle cell disease and thalassemia, yet the relative contributions of hypoxia and cell-free hemoglobin (Hb) to disease progression remain incompletely understood. Patients with hemolytic anemia experience a lifelong cycle of chronic and inter bitten hypoxia that compounds vascular injury driven by extracellular Hb and its degradation products, heme and iron. While the effects of hypoxia and Hb exposure have historically been studied in isolation, the combined impact of sustained, low-level plasma Hb together with chronic hypoxia-more representative of steady-state hemolysis-has been largely overlooked. A rat model incorporating chronic hypoxia with continuous low-dose Hb infusion via an implanted pump demonstrates that even modest plasma Hb concentrations (10-20 µM heme) exert an additive effect on hypoxia-induced PH. This effect is associated with increased adventitial macrophage accumulation, oxidative stress, and inflammation, driving more severe pulmonary vascular remodeling. Building on this model, therapeutic strategies targeting Hb-mediated vascular injury are evaluated, with particular focus on repeated-dose haptoglobin (Hp) therapy, given that Hp is often severely depleted in sickle cell disease. Restoring circulating Hp sequesters plasma Hb into a non-reactive, compartmentalized Hb-Hp complex, limiting NO scavenging and oxidative damage. These mechanistic findings are further linked to functional outcomes through studies of skeletal muscle microvascular oxygen tension and exercise capacity in Berkeley sickle cell disease mice. This review synthesizes findings across these studies to clarify the interplay between hypoxia, macrophage biology, and extracellular Hb in driving pulmonary vascular remodeling and to highlight emerging Hb-targeted therapeutic strategies for hemolysis-associated PH.
2026-08-14 | Augmenting hemopexin-mediated heme scavenging mitigates sepsis-induced acute kidney injury in humanized sickle cell mice.
Sickle cell disease (SCD) is characterized by chronic intravascular hemolysis and depletion of the heme scavenger hemopexin (HPX), generating a high-heme milieu that may increase susceptibility to inflammatory organ injury. Sepsis is a leading cause of acute kidney injury (AKI), yet the contribution of hemolysis-derived free heme to polymicrobial sepsis-associated AKI in SCD remains poorly defined. Using humanized SCD mice, we tested whether augmenting heme clearance via HPX mitigates septic AKI. Low-grade cecal ligation and puncture induced exaggerated systemic inflammation, elevated circulating heme and ferritin, and marked reductions in glomerular filtration rate (GFR) in sickling (hemoglobin SS [HbSS]) mice compared with nonsickling (HbAA) control mice. Septic SS mice also exhibited enhanced renal nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 inflammasome activation, increased oxidative stress, and tubular injury, consistent with heme-driven inflammatory and cytotoxic signaling. Acute administration of purified human HPX reduced circulating heme and ferritin, attenuated cytokine responses, and preserved GFR, indicating that restoration of heme buffering in SCD interrupts kidney injury pathways during septic stress. To achieve sustained heme control, we restored HPX expression using liver-directed delivery of adeno-associated virus serotype 8 (AAV8). AAV8-HPX restored hepatic HPX, reduced basal and sepsis-induced plasma heme levels, conferred protection against kidney dysfunction and tubular stress, and improved survival without evidence of hepatotoxicity. Collectively, these findings identify free heme as a central mediator linking hemolysis to sepsis-associated AKI in SCD, and establish that HPX augmentation via protein replacement or gene therapy is a mechanistically targeted, potentially translatable therapeutic strategy to mitigate heme-driven tissue injury and improve outcomes in SCD-associated sepsis.
2026-02-02 | Luspatercept ameliorates disease phenotype and complications in the Townes mouse model of sickle cell disease.
Preclinical data demonstrating that luspatercept mitigates vaso-occlusive and anemia-related complications in the Townes sickle cell model provide a strong rationale for its evaluation in SCD patients.
2025-12-09 | Thrombomodulin protects against acute vascular and multiorgan injury in sickle cell disease.
Vaso-occlusive episodes (VOEs) in the setting of hyperhemolysis can rapidly evolve into multiorgan failure in sickle cell disease (SCD). Although the mechanisms for rapid progression to multiorgan failure are unclear, a systemic vasculopathy with thrombotic microangiopathy-type features has been described. Reduced thrombomodulin (TM) function is implicated in some thrombotic microangiopathy syndromes. We observed a greater decline in platelet count and hemoglobin concentration and an increase in vascular injury biomarkers within 24 hours of admission for a VOE in 12 patients with SCD with multiorgan failure versus 12 patients without multiorgan failure. We observed decreased TM expression on the lung and kidney vasculature of 3 additional patients with SCD with multiorgan failure compared with a control patient without SCD. Transgenic SCD mice challenged with cell-free hemoglobin had reduced TM function, increased vascular injury biomarkers, and reduced renal cortical blood flow. Infusion of recombinant TM 2 or 24 hours after the challenge restored cortical blood flow and mitigated increases in vascular injury, complement activation, and tubular injury biomarkers, and protected against acute kidney and lung injury. We demonstrated that impaired TM function may be involved in the systemic vasculopathy of SCD-related multiorgan failure, and infusion of recombinant TM may restore vascular function and protect against acute organ damage.
2025-09-26 | Combined haptoglobin and hemopexin therapy for the treatment of cardiopulmonary dysfunction in sickle cell disease.
Hemolysis and the downstream consequences of cell-free hemoglobin (Hb) and heme contribute to the development of sickle cell disease pulmonary hypertension (SCD-PH). The plasma concentrations of Hb and heme scavenger proteins haptoglobin (Hp) and hemopexin (Hpx) in sickle cell patients are observed to be significantly lower than healthy donors. The unchecked exposure to Hb and heme contribute to vasculopathy and aberrant cardiac function. This is consistent with vascular remodeling co-localized within iron rich macrophages. Based on these observations in patients, we hypothesize that a joint Hb and heme scavenger approach, combining Hp + Hpx as a therapeutic will attenuate hemolysis driven SCD-PH progression in a SCD mouse model. To test the hypothesis, we utilized our validated Berk-SS mouse model of SCD-PH driven by a 10-week moderate hypoxia exposure and weekly subcutaneous administration of Hp + Hpx. At study termination, we analyzed changes in cardiopulmonary iron deposition, right ventricular and pulmonary functional parameters, and multi-omic indices associated with SCD-PH. Our data demonstrates that Hp+Hpx improves pulmonary vascular resistance and right ventricular function including stiffness, afterload, cardiac output, ventricular to vascular coupling ratio, pulmonary vascular resistance and medial hypertrophy. Histological evaluation of lung and right ventricular tissue demonstrates attenuation of cardiopulmonary pathology. Finally, a multi-omic analysis of whole lung and heart tissue demonstrates a rebalancing of proteins related to PH, iron, inflammation, and oxidative stress. This data provides strong pre-clinical evidence for the clinical study of combined Hb and heme scavenger proteins in the treatment of PH-associated SCD.
small molecules
2026-09-24 | Beyond Pain: A Pilot Study of Neurodegenerative and Mitochondrial Pathway Alterations in Sickle Cell Disease Using Platelet Proteomics.
Sickle cell disease (SCD) is a systemic disorder marked by chronic pain and neurocognitive deficits, yet the molecular drivers of these neurocognitive features remain poorly defined. Platelets, central to inflammation and vascular homeostasis, may reflect broad pathophysiologic processes in SCD. We performed high-resolution mass spectrometry on ultra-purified platelets from 16 adults with SCD and moderate to severe pain (self-reported ≥ 3/10 in the past year), identifying 4196 proteins, of which 1046 were significant (FDR < 0.05). Unsupervised clustering was used to stratify individuals into high- and low-pain phenotypes. Contrary to expectations, canonical pain pathways were not enriched. Instead, significant alterations were observed in neurodegeneration, mitochondrial metabolism, ATP regulation, mitophagy, and tRNA aminoacylation pathways between high- and low-pain phenotypes. High-pain individuals exhibited elevated levels of proteins involved in proteostasis and neurodegenerative disease processes, whereas low-pain individuals showed increased expression of proteins linked to mitochondrial integrity, neuroprotection, and reduced oxidative stress. Protein-protein interaction networks revealed tightly connected clusters within neurodegenerative and central nervous system-related pathways. Disease association analysis ranked neurodegenerative and mitochondrial pathways above traditional hematologic and nociceptive mechanisms. These findings suggest that platelet proteomics may serve as a peripheral window into PNS or CNS vulnerability and cognitive risk in SCD. The enrichment of tRNA aminoacylation and mitochondrial regulation pathways underscores the metabolic complexity of SCD and highlights novel targets for biomarker development and therapeutic intervention.
2026-09-16 | Prehospital management of pain associated with acute complications of Sickle Cell Disease: a preliminary nationwide cross-sectional study.
We aimed to describe the epidemiology of emergency medical services (EMS) encounters for sickle cell disease (SCD) complications, assess clinical practice patterns, and evaluate factors that may be associated with analgesia administration for SCD-related pain throughout the US. We completed a cross-sectional analysis using a nationwide sample of 9-1-1 advanced life support encounters during 2023 where the EMS clinician impression indicated complications of sickle cell disease. Outcomes of interest included pain scale measurements, pain management, and naloxone administration. Descriptive statistics were computed and stratified by key patient- and encounter-related factors. Among a total of 10,023 EMS encounters for SCD complications, 5.2% were pediatric, 48.6% were female, and 94.2% took place in urban settings. Median patient contact time was 22.2 min (IQR: 15.4-31.0). Pain scale measurements were documented in 73.0% of encounters and analgesia of any kind was administered in 13.5% of cases, including opioids in 11.7%. Naloxone administration was rare (<0.1%). Among patients whose pain scale was ≥7/10, encounters where patient contact lasted 20 min or greater had intravenous access established nearly five-times more often and received any analgesia or opioids roughly ten-times more often. In this large nationwide sample of EMS encounters for SCD complications, we found that administration of analgesia occurred more often during encounters with longer EMS-patient contact. However, low rates of pain control in all cases leaves room for improvement in EMS management of SCD-related pain, perhaps via intranasal analgesia.
2026-09-03 | Proximal tubulopathy in adult sickle cell disease: association of alpha-1 microglobulin.
Sickle cell nephropathy remains a major contributor to morbidity in adults with Sickle Cell Disease (SCD), yet proximal tubular injury remains insufficiently characterized, particularly in African settings. Alpha-1 Microglobulin (A1M), a low-molecular-weight protein, may serve as a sensitive biomarker of proximal tubular dysfunction. The authors conducted a multicentre observational cross-sectional study among 246 adults with stable SCD in Kinshasa, Democratic Republic of the Congo. Proximal tubulopathy was defined as A1M/Cr ≥ 20 mg/g. Measured Glomerular Filtration Rate (mGFR) was assessed by plasma iohexol clearance. Associations were evaluated using a pre-specified multivariable logistic regression model with multiple imputation for missing data. Proximal tubulopathy was present in 48% of participants. After adjustment, vaso-occlusive crises during the previous trimester (aOR = 1.96, 95% CI 1.14-3.35), leg ulcers (aOR = 2.11, 95% CI 1.16-3.82), and albuminuria (log-transformed UACR; aOR = 1.53, 95% CI 1.24-1.88) were independently associated with elevated A1M/Cr. Hydroxyurea use was associated with lower odds of proximal tubulopathy (aOR = 0.54, 95% CI 0.31-0.95). In a model adjusted for albuminuria, no independent associations were observed for markers of hemolysis or measured GFR, suggesting that the effects of these factors on tubular injury may be mediated through glomerular injury or are closely intertwined with it. Sensitivity analyses excluding albuminuria from the model (Tables S2-S5) did show associations with leg ulcer, recent VOC, and systolic blood pressure. Proximal tubular dysfunction is frequent among adults with SCD in this high-burden African setting and was independently associated with markers of disease severity and renal involvement.
2026-08-27 | Colchicine Protects Against Sickle Cell Related Cardiomyopathy: Evidence of the Novel Role of Inflammaging.
Sickle cell disease (SCD) is a globally distributed hereditary red cell disorder with still high mortality. Growing evidence indicates that sickle cell related cardiovascular disease contributes to the early death of adults with SCD. Here, we show that humanized SCD mice developed an age-dependent cardiomyopathy characterized by (i) increased circulating Th17 lymphocytes, Th17 heart infiltration associated with increased plasma IL-17; (ii) collagen deposition and activation of both platelet derived growth factor-B (PDGF-B) and transforming growth factor-β1 (TGF-β1) canonical pathways; (iii) overactivation of heart NF-κB associated with up-regulation of NLRP3 and of inflammatory vasculopathy markers. We then used colchicine (CLC) that acts as anti-inflammatory drug with immunomodulatory effects. In humanized SCD mice, we demonstrated the protective role of low-dose CLC treatment against chronic inflammation and preserving myocardial performance. Of note, we found CLC also attenuating sickle cell related lung damage, suggesting a multiorgan effect of CLC in SCD mice. Our data generate the rationale to further explore CLC as new therapeutic tool to treat early stages of sickle cell cardiomyopathy.
2026-08-06 | An ancient mitochondrial program tunes translation to haem availability.
Anaemia is a major global health burden that affects one-quarter of the human population and annually accounts for over 50 million years of healthy life lost1. It arises from nutritional iron deficiency, hereditary disorders (including thalassaemia and sickle cell disease) and malaria, and is characterized by haemoglobin imbalances2. Haem-the active component of haemoglobin-is both essential and potentially toxic, which necessitates tight control of levels. However, the molecular circuitry that monitors haem levels remains obscure. The cytosolic eIF2α kinase HRI counteracts anaemia amid iron deficiency or thalassaemia3,4 by acting as a gatekeeper of translation during erythroid differentiation, which has been attributed to its haem-binding ability5. Here we uncover that haem scarcity is sensed inside mitochondria through an OMA1-DELE1 axis. Mechanistically, haem deficiency triggers OMA1-dependent mitochondrial release of DELE1. In the cytosol, DELE1 releases inhibitory haem from HRI, which enables modifications in a crucial disordered segment of the kinase. We demonstrate that this sensor-actuator operates across human tissues, including erythroid progenitors, and is evolutionarily conserved down to bloodless invertebrates, thus predating the emergence of haemoglobin-based oxygen transport. Notably, pharmacological manipulation of this system enhances fetal globin expression-a central therapeutic objective in haemoglobinopathies. Together, these results reveal a primordial sentinel system that safeguards against haem-related toxicity from the single-cell to the organismic scale.
gene therapies
2026-09-25 | Intracranial Arteriopathy and Ischemic Brain Injury in Adults With Sickle Cell Disease.
Cerebrovascular injury is a complication of sickle cell disease (SCD), but the spectrum of MRI/MRA abnormalities in adults remains incompletely characterized. We described imaging abnormalities in a consecutive adult SCD clinic cohort undergoing MRI/MRA and examined clinical risk factors and intracranial arteriopathy features associated with parenchymal abnormalities. We retrospectively studied 527 consecutive adults with confirmed SCD who underwent brain MRI/MRA as part of routine follow-up at a tertiary SCD clinic, not restricted to patients with a history of stroke or TIA. Parenchymal outcomes included cortical, lacunar, watershed, and large-vessel territorial infarcts, Fazekas score >1, and global cortical atrophy. For each ischemic or atrophy-related outcome, Model A examined associations with predefined clinical and laboratory factors. Model B added steno-occlusive arteriopathy (SOA) and dilative intracranial arteriopathy (DIA) to evaluate whether vascular imaging features were associated with parenchymal abnormalities beyond clinical factors alone. Mean age was 33.0 ± 12.6 years; 55.6% were female. Ischemic abnormalities included cortical infarcts (13.1%), lacunar infarcts (9.7%), watershed infarcts (5.3%), and large-vessel territorial infarcts (3.4%). SOA was present in 9.3% and was associated with Fazekas score >1, lacunar infarcts, and global cortical atrophy in multivariable models. In targeted analyses, SOA was also associated with watershed and large-vessel territorial infarcts. In a consecutive adult SCD cohort undergoing routine MRI/MRA, ischemic and atrophy-related abnormalities were frequent and heterogeneous overall. SOA, but not DIA, was associated with several parenchymal injury patterns, supporting the potential role of intracranial vascular imaging in refining cerebrovascular phenotyping in adults with SCD.
2026-09-24 | Systemic delivery of phagocytosis-shielded retroviral vectors enables in vivo HSC gene therapy for sickle cell disease.
Ex vivo hematopoietic stem cell (HSC) gene therapy is effective for non-malignant blood disorders including sickle cell disease (SCD), but requires hospitalization, ex vivo cell manipulation, and conditioning. Direct in vivo gene delivery could remove these barriers and widen access. Here, we explore phagocytosis-shielded lentiviral and alpha-retroviral vectors pseudotyped with the baboon endogenous retrovirus glycoprotein variant BaEVRLess for in vivo HSC gene transfer. Vector injection into mobilized humanized mice yielded up to 8.8% gene marking in hCD45+ cells, which chemoselection enriched to 70% of hCD45+ cells and 54% of HSCs. Barcode analysis showed polyclonal reconstitution in over 90% of mice, which remained stable in secondary recipients. For SCD, we targeted BCL11A and ZNF410 selectively in erythroid cells using miRNA-embedded shRNAs to derepress gamma-globin, reaching therapeutically relevant levels of 61.5% of beta-like globins. In summary, BaEVRLess-pseudotyped lentiviral vectors enable clinically relevant in vivo gene transfer and fetal globin induction for SCD.
2026-09-19 | Development of CRISPR_SCD001, an Autologous Hematopoietic Stem Cell Gene Therapy for Sickle Cell Disease after CRISPR-Cas9 Mediated Correction.
We developed CRISPR_SCD001, an autologous cellular therapy in which the pathogenic HBB sickle allele is corrected by CRISPR-Cas9-mediated homology-directed repair using a single-stranded oligodeoxyribonucleotide as DNA donor template. The Drug Product (DP) from Plerixafor-mobilized peripheral-blood CD34+ cells from sickle and healthy donors were used for: 1) pharmacodynamic assessments to interrogate therapeutic potential; 2) evaluation of genotoxicity; and 3) in vivo characterization by a non-GLP toxicology study in NBSGW mice. Large-scale DP lots yielded 89 ± 5 % CD34+ purity with 84 ± 6 % viability. Mean gene correction at HBB was 22 ± 4 % of alleles, with 51 ± 6 % of allelic disruption. Edited erythroid cultures produced 39 ± 5 % adult hemoglobin and 40 ± 6 % fetal hemoglobin, reducing sickle hemoglobin from 89% to 22 ± 6 %. In NBSGW mice, CRISPR_SCD001 engrafted robustly (59 ± 25%), maintained editing frequencies comparable to injected cells (∼20% gene correction), showed polyclonal distribution of the edited cells, and no noteworthy treatment-related toxicity or pathologic evident were found by a blinded histopathology assessment. Our protocol generates a clinical-grade, cryopreserved CD34+ cell product that corrects the sickle mutation, restores anti-sickling hemoglobins, and meets pre-clinical safety criteria, establishing a reproducible manufacturing process suitable for clinical translation. These data support initiation of a first-in-human phase I trial of CRISPR_SCD001 for sickle patients presenting with severe pathology.
2026-09-19 | Gene therapy for hereditary hematological disorders: From clinical breakthroughs to future horizons.
Hereditary hematological disorders, including sickle cell disease, β-thalassemia, and hemophilia, are severe monogenic diseases that impose substantial morbidity and lifelong treatment burdens. Conventional therapies are largely supportive and rarely curative, whereas gene therapy is increasingly transforming the therapeutic landscape by addressing the underlying genetic defects. This review summarizes the major gene therapy strategies currently being developed for hereditary hematological disorders, with a particular focus on gene addition, gene editing, and gene silencing, as well as ex vivo and in vivo delivery platforms. We highlight recent clinical breakthroughs, including approved products for hemoglobinopathies and hemophilia, and discuss emerging approaches such as base editing, prime editing, epigenetic modulation, and lipid nanoparticle-mediated delivery. In addition, we examine the major challenges that continue to limit broader clinical adoption, including immune responses, off-target effects, conditioning-related toxicity, manufacturing complexity, high cost, and limited accessibility. Finally, we outline future directions that may accelerate clinical translation, including improved editing precision, next-generation vector engineering, artificial intelligence-assisted design, scalable manufacturing, and more equitable access to treatment. Together, these advances suggest that gene therapy is steadily moving from experimental innovation toward durable, potentially curative treatment for hereditary hematological disorders.
2026-09-06 | Kenya Sickle Cell Disease Public Health Literacy & Expert Insights Dataset (De-Identified FGDs, KIIs & Surveys)
This dataset contains de-identified qualitative and survey data collected to understand public health literacy, care experiences, and expert perspectives on sickle cell disease (SCD) in Kenya. The collection includes transcripts from Focus Group Discussions (FGDs) with people living with SCD and caregivers, Key Informant Interviews (KIIs) with Ministry of Health officials, healthcare providers, community representatives, and community health promoters (CHPs), as well as technical expert discussions and structured survey responses. The dataset captures themes related to SCD awareness, diagnosis and treatment pathways, access to care, psychosocial challenges, health information needs, health system barriers, and opportunities for improving community-based support and public health communication. All personal identifiers have been removed to protect participant confidentiality. This resource is intended to support research in public health, health communication, digital health, implementation science, and AI-enabled health systems, and provides contextual insights for the development of culturally appropriate interventions and evidence-based decision support tools for sickle cell disease in low-resource settings.
cell therapies
2026-08-23 | Prevalence of Alloimmunization Among Patients With Transfusion-Dependent Thalassemia and Sickle Cell Disease in Salmaniya Medical Complex, Bahrain.
Background Red blood cell (RBC) alloimmunization is a significant complication among patients with transfusion-dependent thalassemia and sickle cell disease (SCD), potentially leading to difficulties in crossmatching, delayed hemolytic transfusion reactions, and hyperhemolysis. In Bahrain, the prevalence of RBC alloimmunization among patients with hemoglobinopathies had not been previously reported. Objective To determine the prevalence of RBC alloimmunization among patients with transfusion-dependent thalassemia and SCD in Bahrain and to compare findings with published regional and international data. Methods A retrospective, cross-sectional study was conducted at Salmaniya Medical Complex (SMC), Bahrain. A total of 311 transfusion-dependent patients, 203 with SCD and 108 with thalassemia, registered between 2016 and 2025 were included. Clinical and laboratory data were extracted from electronic medical records. Patients with a positive indirect antiglobulin test (IAT) showing a consistent reaction strength of 2+ or greater were considered alloimmunized. Descriptive statistics were used to analyze demographic variables and determine the prevalence of alloimmunization. A chi-square test was used to compare alloimmunization rates between the SCD and thalassemia groups. The rates observed in this study were also compared with those reported in other countries using chi-square analysis. A p-value < 0.05 was considered statistically significant. Results The overall prevalence of RBC alloimmunization was 14.8%. Alloimmunization was significantly more prevalent among patients with SCD, with 41 out of 203 (20.2%) testing positive, compared to only 5 out of 108 (4.6%) patients with thalassemia (p < 0.001). Among the 46 alloimmunized patients, 58.7% were male, and 41.3% were female, reflecting the sex distribution of the study population. Blood group O was the most common (54.3%), and 95.5% of patients were Rh-positive. Conclusion The alloimmunization rates observed in this study are consistent with the rates reported in other Middle Eastern countries. Despite extended phenotypic crossmatching, patients with SCD had a significantly higher alloimmunization rate than patients with thalassemia, likely due to disease-related immune activation and differences in transfusion protocols. Adoption of molecular RBC genotyping and comprehensive antibody identification for all alloimmunized patients is recommended to improve transfusion safety in this population.
2026-08-01 | Mixed Myeloid Chimerism and Hemolytic Markers After Nonmyeloablative HCT for Sickle Cell Disease
Sickle cell disease (SCD) is a hemolytic anemia characterized by both intravascular and extravascular hemolysis. Allogeneic hematopoietic cell transplantation (allo-HCT) can be curative in SCD, including in the setting of mixed donor myeloid chimerism. Despite resolution of sickle-related disease complications and chronic anemia following allo-HCT, laboratory evidence of hemolysis may persist. The relationship between mixed myeloid chimerism and residual hemolysis remains incompletely defined and may have implications for newer genetic therapies where a portion of host hematopoietic stem cells remain uncorrected. We evaluated the association between donor myeloid chimerism and hemolytic indices—absolute reticulocyte count (ARC), lactate dehydrogenase (LDH), total bilirubin, and aspartate aminotransferase (AST)—in 88 adult patients with SCD following nonmyeloablative matched-related donor allo-HCT ( ClinicalTrials.gov ID: NCT00061568, NCT02105766). Seventy-three recipients were evaluable at a median follow-up of 5.74 years (range, 1.5-16.97), including 35 (46%) with mixed myeloid chimerism (5-95%). Hemolytic indices inversely correlated with donor myeloid chimerism in the mixed chimerism cohort, reaching statistical significance for all markers except LDH. Although all indices improved compared with pre-HCT values, patients with lower donor chimerism demonstrated higher residual hemolysis, with ARC significantly elevated in the ‘Mixed Low’ (20–50%) compared with ‘Mixed High’ (51–95%) cohort. ARC and LDH remained significantly lower in the ‘Mixed Low’ cohort compared to those with graft failure. Our findings demonstrate a negative correlation between donor myeloid chimerism and residual hemolysis following nonmyeloablative allo-HCT, supporting biologically relevant thresholds of corrected hematopoiesis that may help inform gene therapy approaches in SCD.
2026-07-27 | Evaluating the design and implementation challenges of the Centers for Medicare & Medicaid Services' Cell and Gene Therapy Access Model.
Cell and gene therapies (CGTs) offer potentially curative treatments for conditions like sickle cell disease but pose major affordability and access challenges for Medicaid mainly due to multimillion-dollar upfront prices. In response, the Centers for Medicare & Medicaid Services (CMS) introduced the CGT Access Model, a purchasing approach that leverages the Medicaid Drug Rebate Program to implement multistate, outcome-based agreements for CGTs. Through the Model, CMS negotiates core terms with manufacturers, states adopt these terms through rebate agreements, and CMS coordinates data collection and evaluation. The initiative aims to expand access, improve clinical outcomes, and generate long-term cost savings by aligning payment with demonstrated therapeutic benefit. However, critical uncertainties remain, including outcome-based agreement design, access policy standards, moral hazard risks, fertility-related barriers, out-of-state care challenges, and challenges with data collection. Although imperfect, the CGT Access Model marks an important step toward integrating sustainable financing of high-cost, transformative therapies into public insurance programs.
2026-07-23 | Transplant versus no transplant outcome in adolescents and adults with sickle cell disease eligible for allogeneic hematopoietic stem cell transplantation.
Hematopoietic stem cell transplantation (HSCT) remains the only curative option for sickle cell disease (SCD), but its use in adolescents and adults is limited by toxicity concerns. We evaluated the risk-benefit profile of HSCT in this population through a comparative analysis of transplant versus nontransplant strategies. HSCT was analyzed as a time-dependent variable in consecutive adolescents and adults with an indication for transplantation who were referred for HSCT counseling. At the last follow-up, patients had either undergone HSCT or not. HSCT procedures involved matched related donor (MRD) transplants after myeloablative or non-myeloablative conditioning, and haploidentical transplants after reduced-intensity conditioning. The primary endpoints were overall survival (OS) and composite event-free survival (cEFS), calculated from the initial consultation. Events included death, grade III-IV acute or moderate-to-severe chronic graft-versus-host disease (GVHD), graft rejection, overt stroke, third hospitalized painful crises within two years, acute chest syndrome (ACS), delayed hemolytic transfusion reaction, or initiation of new SCD modifying therapy. Ninety-four patients were included (median follow-up: 2.9 years), of whom 58 underwent HSCT. The 2-year OS was 98% with HSCT versus (vs.) 97% without HSCT (P = 0.55). cEFS was significantly higher post-transplant (72% vs. 28%, P < 0.0001), with marked reduction in painful crises and ACS. Among patients who underwent transplantation, the 2-year rejection-free survival from the time of transplant was 91% for MRD and 82% for haploidentical HSCT (P = 0.40). HSCT substantially improves cEFS without excess short-term mortality, supporting its broader use in adolescents and adults with SCD, particularly when an MRD is available.
2026-07-16 | Design, rationale, and baseline patient characteristics for the Sickle Cell Disease and CardiovAscular Risk-Red cell Exchange (SCD-CARRE) trial.
Despite wide utilization of automated red blood cell exchange (RBCX) transfusion in adult patients with sickle cell disease (SCD), no consensus or quality efficacy data exist on its use. The Sickle Cell Disease and CardiovAscular Risk- Red cell Exchange (SCD-CARRE) trial tests the hypothesis that an automated chronic RBCX transfusion strategy reduces acute health care encounters and death while improving quality of life and end-organ function (cardiac, pulmonary and renal) in participants with SCD that are at high risk of death. Adult patients with SCD with elevated tricuspid regurgitant jet velocity (TRV) and/or chronic kidney disease were considered to be at high risk of death and were randomly assigned to RBCX plus standard of care vs standard of care alone. Participants assigned to RBCX received 12 months of exchange transfusions to maintain target pretransfusion hemoglobin S% < 30%, post-transfusion hemoglobin S% < 20%, and post-transfusion hemoglobin concentration ≥10 g/dL. All study participants were managed according to NHLBI/ASH/ATS Expert Panel guidelines. The primary endpoint was the number of SCD acute health care encounters or death over 13 months. Secondary endpoints included measures of cardiovascular and renal function, exercise capacity, patient reported outcomes (all collected at baseline, and months 4, 8, and 12), and transfusion-related adverse events (collected monthly). Between 2020 and 2025, the SCD-CARRE trial randomized 173 participants at 23 sites across 3 countries. Enrolled participants had mean (SD) age of 45.8 (11.8) years and 54% were female. At baseline, participants had average TRV of 2.8 (0.5) m/s such that 45.9% had a TRV between 2.5 to 2.9 m/sec and 28.1% had a TRV ≥ 3.0 m/sec. The median (Q1, Q3) eGFR in this cohort was 60 (36, 110) mL/min/1.73 m2. The median (Q1, Q3) 6-minute walk test distance was 375 meters (309, 439), the median daily steps were 3,728 (2,187, 5,821), and participants experienced a median (Q1, Q3) of 2 (1, 5) pain episodes in the year prior to randomization. The trial results are pending. The SCD-CARRE trial successfully enrolled a cohort of n = 173 adults with SCD. This study highlights a rationale to evaluate the effect of automated chronic RBCX transfusion strategy plus standard of care as compared to standard of care alone in SCD patients at high risk of death with a focus on patient centered outcomes, preservation of cardiovascular function, end-organ complications and death. ClinicalTrials.gov, Identifier: NCT04084080, https://clinicaltrials.gov/study/NCT04084080.
other
2026-06-01 | Adaptive Immune Remodeling in Sickle Cell Disease: Linking Hemolysis-Driven Inflammation to Immune Dysfunction.
Sickle cell disease (SCD) is increasingly acknowledged not only as a hemoglobinopathy but also as a disorder of immune remodeling driven by persistent hemolysis and chronic inflammation. In this perspective review, we propose a mechanistic scaffold in which hemolysis-associated damage-associated molecular patterns (DAMPs) initiate sustained innate immune activation that reshapes bone marrow niche, i.e., alter hematopoietic stem and progenitor cell fate, alters lymphopoiesis, and progressively remodels adaptive immunity. We discuss emerging evidence linking chronic inflammatory signaling to T-cell activation, altered helper T-cell polarization, impaired germinal center dynamics, and depletion of memory B-cell compartments. We further highlight age-dependent immune remodeling across pediatric and adult SCD populations and discuss how these alterations may contribute to impaired vaccine response, increased susceptibility to infection, and transfusion-related alloimmunization. By integrating insights from hematopoiesis, inflammation, and adaptive immunity, this perspective reframes SCD-associated hemolysis and immune dysfunction as a central component of disease pathophysiology and identifies potential directions for future immunomodulatory and vaccine-focused therapeutic strategies..
2026-01-03 | Anti-IL-18 immunotherapy decreases inflammatory and vaso-occlusive responses in mice with sickle cell disease.
Sickle cell disease (SCD) is characterized by inflammatory and vaso-occlusive processes that drive acute crises and progressive organ damage. Interleukin-18 (IL-18), elevated in patients with SCD and mouse models, contributes to these pathological mechanisms. We evaluated the effects of acute and prolonged IL-18 blockade using the SK113AE-4 monoclonal antibody in Townes and Berkeley SCD mice. Acute IL-18 neutralization reduced tumor necrosis factor-alpha (TNF-α)-induced microvascular leukocyte recruitment and prevented hypoperfusion, indicating that modulation of inflammatory signaling improves physiological responses in SCD. Prolonged anti-IL-18 immunotherapy for 6 weeks decreased circulating TNF-α and IL-10 and reduced hepatic macrophage infiltration, but did not prevent liver fibrosis, iron deposition, or alter biochemical markers of hemolysis or hepatic/renal injury. As such, IL-18 blockade attenuates vascular inflammation and vaso-occlusive-like events but may be insufficient to prevent SCD-related liver injury under the conditions tested. In contrast, in our previous study, anti-IL-1β immunotherapy provided added liver protection, highlighting potentially divergent cytokine pathways in SCD. Collectively, these results support IL-18 as a therapeutic target to reduce vascular inflammation and vaso-occlusive processes, and suggest that combined inflammasome cytokine-targeted or multiapproach strategies may be required to prevent organ damage in SCD.
2025-12-03 | Managing acute myeloid leukemia in the context of sickle cell anemia and suspected Fanconi anemia in Tanzania: a case report.
The transformation of Fanconi anemia into a hematological malignancy is consistent with the natural history of the disease. Few cases have been reported on acute myeloid leukemia, and even fewer cases involving coexistence with sickle cell anemia. Acute myeloid leukemia development is postulated to follow a multihit hypothesis where preleukaemic cells progress into leukemia through a second promotional mutation. Fever is a predominant clinical presentation, with blasts usually observed on peripheral blood smear and the immunophenotype confirmed with flow cytometry. In this case report from Tanzania, we present a case of acute myeloid leukemia with a failed induction in a patient with Sickle cell anemia and suspected Fanconi anemia. A 6-year-old Haya boy from northern Tanzania presented to Muhimbili National Hospital with a congenital malformation of the left hand, short stature, and multiple café-au-lait spots distributed over the trunk, face, and limbs. He had experienced recurrent fever for 8 months, accompanied by headache, weight loss, and abdominal distension. Laboratory evaluation confirmed acute myeloid leukemia and sickle cell anemia with clinically suspicious features of Fanconi anemia. The patient was initiated on institutional treatment for acute myeloid leukemia. He had a failed induction and subsequently transitioned to home-based palliative care after prognostic counseling with the family. Thereafter, he had several admissions, mostly for blood product support, and eventually died 7 months post-discharge. The onset of acute myeloid leukemia in this case could be attributed to a malignant transformation from an underlying cancer predisposition syndrome. Our particular focus was on the leukemia treatment response where we observed a failed induction, prompting the need for alternative treatment approaches in this category of patients with acute myeloid leukemia in order to realize better treatment outcomes.
2025-05-15 | Rpl13a snoRNAs U34 and U35a: New Targets for Sickle Cell Disease Complications.
In sickle cell disease (SCD), erythrocyte reactive oxygen species (ROS) production and oxidative stress play a critical role in vaso-occlusion, a hallmark of SCD. Small noncoding nucleolar RNAs (snoRNAs) of the Rpl13a locus have been described as regulators of ROS levels. However, whether Rpl13a snoRNAs are present in sickle red blood cells (RBCs) and regulate ROS levels and whether they contribute to SCD pathophysiology remain unknown. To determine whether sickle RBC ROS levels are associated with Rpl13a snoRNA levels and identify the mechanism by which they regulate ROS and snoRNAs' effects on SCD hemodynamics, we used human RBCs, Rpl13a snoRNA knockout sickle mice, K562 U32a, U33, U34, U35a, and the control U25 knockout mutants generated by CRISPR-Cas9 (Clustered Regularly Interspaced Short Palindromic Repeats/Cas9 protein)-targeted genome editing, and genetic targeting with antisense oligonucleotides. Excessive ROS production in sickle RBCs of patients with SCD is associated with high Rpl13a snoRNAs U32a, U33, U34, and U35a levels. U32a, U34, and U35a regulate ROS and hydrogen peroxide levels in sickle erythroid populations by modulating peroxidase activity. This was due to U32a- and U34-guided 2'-O-methylation on Prdx2 (peroxiredoxin 2) messenger RNA, a modification conveyed by fibrillarin during erythropoiesis, subsequently reducing Prdx2 expression and activity. The snoRNA U35a impaired Prdx2 expression/activity but independently of Prdx2 messenger RNA 2'-O-methylation. Excess sickle RBC ROS increased in turn Rpl13a snoRNAs levels. In vivo targeting combinations of U34+U35a and U32a+U34+U35a in sickle mice with antisense oligonucleotide blunted RBC ROS generation, improved erythropoiesis and anemia, alleviated leukocytosis and endothelial damage, diminished cell adhesion in inflamed vessels and vaso-occlusion, restored blood flow, and reduced animal mortality. Rpl13a snoRNAs U34 and U35a specifically increase ROS levels, which, in turn, regulate snoRNA expression, in sickle erythroid cells, modulating Prdx2 expression/activity, subsequently impairing hemodynamics. Targeted U34+U35a with antisense oligonucleotide may represent a novel and safe therapy to ameliorate erythropoiesis and downstream events in SCD.
2025-05-04 | Serotype specific pneumococcal vaccine effectiveness in children with sickle cell disease: A two-decade analysis.
Sickle cell disease (SCD) is the most common genetic hematologic disease globally and children with SCD are at increased risk for pneumococcal disease. We utilized data from population-based enhanced surveillance for invasive pneumococcal disease (IPD) in children <18 years of age in Massachusetts from 2002 to 2020. We calculated incidence rates (IR) among children with SCD using bootstrapping resampling and incidence rate ratios (IRR) for pre- and post-PCV13 periods. Vaccine effectiveness (VE) was calculated as 100*(1-IRR), and PCV13 vaccine failure probability was predicted using a random forest model. Children with SCD had higher IR during both pre-/post-PCV13 periods compared with otherwise healthy children 240.0/100,000 versus 4.6/100,000 in pre-PCV13 period (2002-2009); 172.7/100,000 versus 1.9/100,000 in post-PCV13 period (2011-2020), respectively. After widespread use of PCV7 for a decade, a modest reduction of 28.1 % (95% CI 25.9-37.2%) in the incidence of overall IPD during the post-PCV13 period was observed in children with SCD, whereas a more substantial 59.5% (96% CI 57.8-61.4%) reduction was observed in otherwise healthy children. There was a 60.8% (95% CI 55.2%-NA) reduction in the incidence of VST13 IPD in children with SCD and an 83.0% (95% CI 80.67-85.63%) reduction in children without underlying health condition. Overall, 61.1% of the remaining IPD among children with SCD were due to non-PCV13 serotypes (8, 10A, 15A,15B, 22F, 23B), many of which are included in expanded valency vaccines. Children with SCD continue to have higher rates of IPD compared with otherwise healthy children despite vaccination. Majority of the remaining disease is due to serotypes not included in vaccine formulations that have been used for the last two decades. Our study highlights the potential value of expanded valency vaccines and importance of risk-based vaccination strategies tailored for this vulnerable population.
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Drug Discovery Landscape
111 orphan drug designations for Sickle cell disease and related diseases, including 8 approved therapies.
111 orphan drug designations for Sickle cell disease and related diseases, including 8 approved therapies.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
tebapivat | small molecules | FDA | Agios Pharmaceuticals, Inc. | |
desidustat | small molecules | FDA | — | Zydus Healthcare (USA), LLC, |
Nangibotide | peptides | EMA | — | Inotrem |
fetal hemoglobin activator cereblon (CRBN) E3 ligase-modulating drug | small molecules | FDA | Bristol-Myers Squibb | |
(lE, 6E)-1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6- heptadiene-3,5-dione) | small molecules | FDA | Vascarta Inc. | |
autologous CD34+ cell therapy comprised of hematopoietic stem and progenitor cells base edited with one guide RNA and a single messenger RNA encoding an adenine base editor | cell therapies | FDA | Beam Therapeutics | |
rilzabrutinib | small molecules | FDA | Sanofi US Services Inc. | |
Mitapivat sulfate | small molecules | EMA | Agios Netherlands B.V. | |
(8'-hydroxy-6'-oxo-3'-phenyl-6'H-spiro[cyclopentyl-1,5'-indolazine]-7'-carbonyl) glycine | small molecules | FDA | — | KIND Pharmaceuticals LLC |
ex vivo manufactured allogeneic red blood cells derived from hematopoietic progenitor cells | cell therapies | FDA | — | Safi Biotherapeutics, Inc. |
pyrindinyl benzaldehyde | small molecules | FDA | — | Illexcor Therapeutics, LLC |
l-arginine | other | FDA | Emory University | |
Beta-nicotinamide mononucleotide | small molecules | FDA | — | Nuvamid SA |
a recombinant, humanized single variable domain on a heavy chain (VHH) bispecific antibody that binds with high affinity to human properdin and human serum albumin | antibodies | FDA | Alexion Pharmaceuticals, Inc. | |
Tarperprumig | antibodies | EMA | Alexion Europe | |
Nicotinamide mononucleotide | small molecules | EMA | — | LGD |
Autologous CD34+ hematopoietic stem and progenitor cells edited by CRISPR/CAS12a at the HBG1 and HBG2 promoters | cell therapies | FDA | Editas Medicine, Inc. | |
Epeleuton | small molecules | EMA | Afimmune Limited | |
2-[(1,3-Benzoxazol-2-yl)amino]-N-[2-(2-hydroxyethoxy)ethyl]-1-methyl-1H-benzimidazole-5- carboxamide monophosphate | small molecules | FDA | — | Astellas Pharma Global Development, Inc. |
15(S)-hydroxy-(5Z,8Z,11Z,13E,17Z)-eicosapentaenoic acid ethyl ester (15(S)-HEPE-EE) | small molecules | FDA | Afimmune | |
Inclacumab | antibodies | FDA | Global Blood Therapeutics, Inc. | |
a hemoglobin S polymerization inhibitor | small molecules | FDA | Global Blood Therapeutics, Inc. | |
(S)-Pociredir | small molecules | EMA | Pharma Gateway AB | |
naproxcinod | small molecules | FDA | — | Fera Pharmaceuticals, LLC |
Pociredir | small molecules | FDA | Fulcrum Therapeutics, Inc. | |
gene-corrected (gc) HBB beta-globin gene variant for SCD drug product | combination | FDA | Kamau Therapeutics, Inc. | |
2-(2-{[2-(1H-benzimidazol-2-yl)ethyl]amino}ethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-oxazole-4-carboxamide trihydrochloride | small molecules | EMA | Vifor France S.A. | |
Autologous CD34+ hematopoietic stem and progenitor cells transfected with zinc finger nuclease mRNAs SB-mRENH1 and SB-mRENH2 | gene editing enzymes | EMA | Yes Pharmaceutical Development Services GmbH | |
ferroportin inhibitor | small molecules | FDA | Vifor Pharma, Inc. | |
pyrindinyl benzaldehyde | small molecules | FDA | — | Illexcor Therapeutics, LLC |
Autologous CD34+ cells transduced ex vivo with a lentiviral vector containing a modified gamma-globin gene | gene therapies | EMA | — | PPD Bulgaria EOOD |
mitapivat | small molecules | FDA | Agios Pharmaceuticals, Inc. | |
Rifaximin | small molecules | FDA | Salix Pharmaceuticals, Inc. (a division of Bausch Health US, LLC) | |
Decitabine, tetrahydrouridine | small molecules | EMA | Novo Nordisk A/S | |
(S)-1-(5-((2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl)sulfonyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrol-2(1h)-yl)-3-hydroxy-2-phenylpropan-1-one | small molecules | EMA | Novo Nordisk A/S | |
L-citrulline | small molecules | FDA | Asklepion Pharmaceuticals, LLC | |
rADAMTS13 / apadamtase alfa (INN) | proteins | FDA | Takeda Pharmaceuticals U.S.A., Inc. | |
Hemopexin (Human) | proteins | FDA | CSL Behring | |
a recombinant humanized Fc effector function null IgG1 antibody with kappa light chains (IgG1) that selectively binds to E-selectin to inhibit binding to cellular proteins containing carbohydrate structures with a sialyl Lewis X (sLex) deter | antibodies | FDA | Pfizer Inc. | |
6-{(1S)-1-[(2-Amino-6-fluoroquinolin-3-yl)oxy]ethyl}-5-(1H-pyrazol-1-yl)pyridin-2(1H)-one | small molecules | FDA | — | Pfizer, Inc. |
Tovinontrine | small molecules | EMA | [INACTIVE] TMC Pharma (EU) Limited | |
Hemopexin, human | proteins | EMA | CSL Behring GmbH | |
exagamglogene autotemcel [Casgevy] | combination | FDA | Approved | Vertex Pharmaceuticals Inc. |
Sodium Nitrite | small molecules | FDA | AdimaBio LLC | |
etavopivat | small molecules | FDA | Novo Nordisk Inc. | |
Autologous CD34+ cells transduced with gamma globin lentiviral vector | gene therapies | FDA | Cincinnati Children’s Hospital Medical Center | |
Autologous CD34+ hematopoietic stem cells with a CRISPR-edited erythroid enhancer region of the BCL11A gene [Casgevy] | combination | EMA | Approved | Vertex Pharmaceuticals (Ireland) Limited |
Autologous CD34+ hematopoietic stem and progenitor cells transfected with zinc finger nuclease messenger RNAs SB-mRENH1 and SB-mRENH2 | gene editing enzymes | FDA | Sangamo Therapeutics, Inc. | |
deferoxamine | small molecules | FDA | Theris Medical | |
Benserazide hydrochloride | small molecules | EMA | Isabelle Ramirez | |
olinciguat | small molecules | FDA | Cyclerion Therapeutics, Inc. | |
Docosahexaenoic acid ethyl ester | small molecules | EMA | TurnKey PharmaConsulting Ireland Limited | |
sirolimus | small molecules | FDA | Rare Partners srl Impresa Sociale | |
Sirolimus | small molecules | EMA | Rare Partners srl Impresa Sociale | |
Decitabine and tetrahydrouridine | small molecules | EMA | Ulrich Muehlner | |
6-[(3S,4S-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl]-3-tetrahydropyran-4-yl-7H-imadazo[1,5-a]pyrazin-8-one | small molecules | FDA | Imara Inc. | |
2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde [Oxbryta] | small molecules | EMA | Approved | Pfizer Europe MA EEIG |
Hepcidin | peptides | EMA | — | La Jolla Pharmaceutical II B.V. |
decitabine and tetrahydrouridine | small molecules | FDA | Novo Nordisk Inc. | |
dodecafluoropentane emulsion | other | FDA | — | NuvOx Pharma |
Voxelotor [Oxbryta] | small molecules | FDA | Approved | Global Blood Therapeutics, Inc. |
prasugrel hydrochloride | small molecules | FDA | Eli Lilly | |
docosahexaenoic acid | small molecules | FDA | Micelle BioPharma, Inc. | |
sevuparin | small molecules | FDA | Modus Therapeutics | |
hydroxyurea | small molecules | FDA | Ebelle D'Ebelle Pharmaceuticals LLC | |
Sevuparin sodium | other | EMA | Modus Therapeutics AB | |
5-(hydroxymethyl)-2-furaldehyde [BAX 555] | small molecules | EMA | BAXALTA INNOVATIONS GmbH | |
pegylated carboxyhemoglobin bovine | proteins | FDA | Prolong Pharmaceuticals, LLC | |
6-((3S,4S)-4-Methyl-1-pyrimidin-2-ylmethyl-pyrrolidin-3-yl-1-(tetrahydro-pyran-4-yl)-1,5-dihydro-pryazolo[3,4-d]pyrimidin-4-one | small molecules | FDA | Cardurion Pharmaceuticals, Inc. | |
Betibeglogene autotemcel [Zynteglo] | gene therapies | EMA | bluebird bio (Netherlands) B.V. | |
lovotibeglogene autotemcel [Lyfgenia] | gene therapies | FDA | Approved | Genetix Biotherapeutics Inc. |
human haptoglobin | proteins | FDA | — | BioProducts Laboratory Limited |
Rivipansel | small molecules | EMA | FGK Representative Service GmbH | |
hydroxycarbamide (hydroxyurea) [Siklos] | small molecules | FDA | Approved | Theravia Pharma |
recombinant humanized IgG1k monoclonal antibody to human invariant T cell receptor (iTCR) | antibodies | FDA | NKT Therapeutics, Inc. | |
Poloxamer 188 [ANX-188 (purified poloxamer 188) Injection] | small molecules | EMA | Theradex (Europe) Limited | |
extract of sorghum bicolor extract | other | FDA | Invenux, LLC | |
carbon monoxide | small molecules | FDA | Hillhurst Biopharmaceuticals, Inc. | |
Crizanlizumab [Adakveo] | antibodies | EMA | Novartis Europharm Limited | |
Levoglutamide | small molecules | EMA | Emmaus Medical Europe Limited | |
Human erythrocytes encapsulating inositol hexaphosphate | small molecules | EMA | — | ERYtech Pharma S.A. |
Human haptoglobin | proteins | EMA | — | Kedrion S.p.A. |
pentosan polysulfate sodium | small molecules | FDA | Vanguard Therapeutics, Inc. | |
Deferiprone | small molecules | EMA | Chiesi Farmaceutici S.p.A. | |
pegylated carboxyhemoglobin | proteins | FDA | Sangart, Inc. | |
Pegylated carboxyhaemoglobin | proteins | EMA | Voisin Consulting Life Sciences | |
2,2-dimethylbutyric acid, sodium salt | small molecules | EMA | Isabelle Ramirez | |
(1R,3R,4R,5S)-3-O-[2-O-benzoyl-3-O-(sodium(2S)-3-cyclohexyl-propanoate- | small molecules | FDA | GlycoMimetics, Inc. | |
pentosan polysulfate sodium | small molecules | FDA | TRF Pharma, Inc. | |
nitric oxide | small molecules | FDA | Mallinckrodt Pharmaceuticals Ireland Ltd. | |
sodium 2, 2 dimethylbutyrate | small molecules | FDA | HemaQuest Pharmaceuticals, Inc. | |
crizanlizumab [ADAKVEO] | antibodies | FDA | Approved | Novartis Pharmaceuticals Corporation |
varespladib sodium | small molecules | FDA | Anthera Pharmaceuticals, Inc. | |
sodium nitrite | small molecules | FDA | Hope Pharmaceuticals | |
5-hydroxymethyl-2-furfuraldehyde | small molecules | FDA | Baxalta US, Inc. | |
Extract of Sorghum bicolour leaf, Pterocarpus osun stem, Piper guineense seed and Caryophylli flower | other | EMA | — | Xechem UK Ltd |
oral unfractionated heparin | small molecules | FDA | TRF Technologies, Inc. | |
niprisan | other | FDA | — | Xechem International, Inc. |
Hydroxycarbamide [Siklos] | small molecules | EMA | [INACTIVE] Addmedica | |
N-[4-bromo-2-(1H-1,2,3,4-tetrazol-5-yl)phenyl]-N'-[3,5-bis(trifluoromethyl)phenyl]urea | small molecules | FDA | — | NeuroSearch A/S |
L-glutamine [Endari] | small molecules | FDA | Approved | Emmaus Medical, Inc. |
Bis(4-fluorophenyl)phenylacetamide | small molecules | FDA | ICAgen Inc. | |
Fructose-1,6-diphosphate | small molecules | FDA | — | Questcor Pharmaceuticals, Inc. |
Clotrimazole | small molecules | FDA | Brugnara, Carlo M.D. | |
Arginine butyrate | small molecules | FDA | Vertex Pharmaceuticals Inc. | |
sodium phenylbutyrate | small molecules | FDA | — | Medicis Pharmaceutical Corp. |
Synthetic derivative of 16-hydroxy-9Z, 12Z, 14E-octadecatrienoic acid | small molecules | FDA | — | Omex International, Inc. |
Lysine acetylsalicylate injectable | small molecules | FDA | — | G.D. Searle & Company |
poloxamer 188 (purified) | small molecules | FDA | Mast Therapeutics Inc. | |
Cetiedil citrate injection | small molecules | FDA | — | Baker Cummins Pharmaceuticals, Inc. |
substituted benzaldehyde that binds to the oxy-conformation of Hb between amino terminal residues of the alpha-subunits | small molecules | FDA | — | Burroughs Wellcome Company |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
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