Rap-536, a Murine Luspatercept Analog Ameliorates Anemia and Vaso-Occlusion in Experimental Model of Sickle Cell Disease
Notice bibliographique
Résumé
Introduction Sickle cell disease (SCD) is a hereditary hemoglobinopathy characterized by chronic hemolytic anemia and vaso-occlusive crises (VOC), leading to significant morbidity and mortality. Luspatercept is a ligand trap receptor indicated in thalassemia and myelodysplastic disease that restores effective erythropoiesis by reducing the inhibitory effects of transforming growth factor-beta (TGF-β) superfamily members, including GDF-11. Here we investigate the expression of GDF-11 in SCD patients and the role of RAP-536, a murine analog of luspatercept, in modulating anemia and VOC in SCD models, alone and/or in combination with hydroxyurea (HU) and epigenetic modulators Tazemetostat (TZM) and FTX6058, inducers of fetal hemoglobin (HbF). Methods We assessed GDF11 levels in plasma samples from SCD patients, healthy donors, and patients with other hemolytic anemias. Expression of GDF11 and pSMAD2 were evaluated in the spleen of Townes HbSS mice by immunohistochemistry. HbSS mice were treated with RAP-536 (1 or 10 mg/kg i.p. twice a week for 8 weeks), alone or in combination with hydroxyurea (100 mg/kg oral QD), TZM (250 mg/kg oral QD) and FTX6058 (20 mg/kg oral QD). Hematological, biochemical, and histological parameters were measured to assess treatment effects. Results Plasma GDF11 levels were significantly increased in SCD patients (27.7 pg/ml) when compared to healthy donors (5.0 pg/ml, p<0.01) and other hemolytic anemias (8.0 pg/ml). HbSS mice showed higher GDF11 expression in the spleen compared to HbAA mice, which correlated with SMAD2 phosphorylation. In HbSS mice, RAP-536 increased red blood cell (RBC) count and hemoglobin levels, decreased reticulocytes and ameliorated hemolytic markers, reducing lactate dehydrogenase (LDH), bilirubin as well as plasma free hemoglobin and plasma free heme. Likewise, tissue vascular congestion in hypoxia-induced VOC were reduced in the liver, lungs, and kidneys of HbSS mice upon RAP-536 treatment. Using ektacytometry, in vivo treatment of HSS mice by RAP-536 improved RBC deformability, as indicated by increased elongation index at 3Pa and 20Pa. This improvement correlated with enhanced oxygen carrying capacity in HbSS mice treated with RAP-536, with significant increases in total hemoglobin (+18.4%, p<0.05), oxygenated hemoglobin (+41.3%), oxygen saturation (+40.9%), oxygen content (+65.2%), and oxygen carrying capacity (+14.0%, p<0.05). All these effects were independent of HbF modulation. In contrast, RAP-536 significantly reduced blood reactive oxygen species (ROS) levels which may contribute to the reduction of VOC and improvement of erythropoiesis. RAP-536 reduced splenomegaly and improved erythropoietic maturation in spleen and bone marrow, indicated by a higher proportion of orthochromatic erythroblasts and reticulocytes (Ter-119+CD71− Ery.C) compared to late basophilic and polychromatic erythroblasts (Ter-119+CD71+ Ery.B). ROS level reduction was associated to increase in Nrf2 levels (which regulates anti-oxidant stress) and GATA-1 expression in erythroid precursor populations. In order to further improve the effects of RAP-536 (since it did not increase HbF), we evaluated the effects of RAP-536 combination with HU, TZM or FTX6058. First, we show that HU, TZM and FTX6058 induced HbF, with a synergistic effect observed only in RAP-536 and FTX6058 combination. Likewise, combination therapy with TZM or FTX6058 further enhanced RBC count, Ery.C cells and reduced reticulocyte counts and bilirubin levels. No additive or synergistic effect was observed to reduce ROS levels. In a hypoxia/re-oxygenation VOC model, the reduction of sickling observed with RAP-536 was additive with that observed with TZM or FTX6058. Conclusion These pre-clinical data highlight the potential of luspatercept (RAP-536) as a therapeutic agent in SCD, demonstrating significant improvements in ineffective erythropoiesis, reduction of hemolysis and ROS levels, and amelioration of VOC events independently of HbF induction. Effects on chronic complications are currently being investigated. The observed synergy with HbF inducers like HU, TZM and FTX6058 suggests potential combination strategies to enhance therapeutic outcomes. These findings warrant clinical evaluation of luspatercept in SCD patients, aiming to address both anemia and vaso-occlusive complications in this patient population with high unmet medical need.
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Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,001 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,001 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,003 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».