Short-term administration of JAK2 inhibitors reduces splenomegaly in mouse models of β-thalassemia intermedia and major

Casu, Carla; Presti, Vania Lo; Oikonomidou, Paraskevi Rea; Melchiori, Luca; Abdulmalik, Osheiza; Ramos, Pedro Luiz; Rivella, Stefano

doi:10.3324/haematol.2017.181511

Cited by 29 publications

(29 citation statements)

References 13 publications

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“…1b) [53]. The inhibition of JAK2 in TDT and NTDT mouse models not only improved ineffective erythropoiesis but also reversed splenomegaly [54,55]. Based on these findings, it has been suggested that the use of ruxolitinib could benefit thalassemia patients.…”

Section: Jak2 Inhibitorsmentioning

confidence: 98%

Beta Thalassemia: New Therapeutic Options Beyond Transfusion and Iron Chelation

Motta

Bou‐Fakhredin

Taher

et al. 2020

Drugs

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Hemoglobinopathies are among the most common monogenic diseases worldwide. Approximately 1-5% of the global population are carriers for a genetic thalassemia mutation. The thalassemias are characterized by autosomal recessive inherited defects in the production of hemoglobin. They are highly prevalent in the Mediterranean, Middle East, Indian subcontinent, and East and Southeast Asia. Due to recent migrations, however, the thalassemias are now becoming more common in Europe and North America, making this disease a global health concern. Currently available conventional therapies in thalassemia have many challenges and limitations. A better understanding of the pathophysiology of β-thalassemia in addition to key developments in optimizing transfusion programs and iron-chelation therapy has led to an increase in the life span of thalassemia patients and paved the way for new therapeutic strategies. These can be classified into three categories based on their efforts to address different features of the underlying pathophysiology of β-thalassemia: correction of the globin chain imbalance, addressing ineffective erythropoiesis, and improving iron overload. In this review, we provide an overview of the novel therapeutic approaches that are currently in development for β-thalassemia.

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Section: Jak2 Inhibitorsmentioning

confidence: 98%

Beta Thalassemia: New Therapeutic Options Beyond Transfusion and Iron Chelation

Motta

Bou‐Fakhredin

Taher

et al. 2020

Drugs

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“… 15 The inhibition of JAK2 in TDT and NTDT mouse models improved ineffective erythropoiesis and reversed splenomegaly. 16 A phase 2a study (NCT02049450) assessed ruxolitinib efficacy and safety in TDT patients with spleen enlargement. A decrease in spleen size from baseline was observed in ruxolitinib-treated patients.…”

Section: Pharmacological Therapiesmentioning

confidence: 99%

Innovative Treatments for Rare Anemias

et al. 2021

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Rare anemias (RA) are mostly hereditary disorders with low prevalence and a broad spectrum of clinical severity, affecting different stages of erythropoiesis or red blood cell components. RA often remains underdiagnosed or misdiagnosed, and treatment options have been limited to supportive care for many years. During the last decades, the elucidation of the molecular mechanisms underlying several RA paved the way for developing new treatments. Innovative treatments other than supportive care and allogeneic bone marrow transplantation are currently in clinical trials for β-thalassemias, sickle cell disease (SCD), and congenital hemolytic anemias. Recently, luspatercept, an activin receptor ligand trap targeting ineffective erythropoiesis, has been approved as the first pharmacological treatment for transfusion-dependent β-thalassemia. L-glutamine, voxelotor, and crizanlizumab are new drugs approved SCD, targeting different steps of the complex pathophysiological mechanism. Gene therapy represents an innovative and encouraging strategy currently under evaluation in several RA and recently approved for β-thalassemia. Moreover, the advent of gene-editing technologies represents an additional option, mainly focused on correcting the defective gene or editing the expression of genes that regulate fetal hemoglobin synthesis. In this review, we aim to update the status of innovative treatments and the ongoing trials and discuss RA treatments' future directions. Interestingly, several molecules that showed promising results for treating one of these disorders are now under evaluation in the others. In the near future, the management of RA will probably consist of polypharmacotherapy tailored to patients' characteristics.

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“…Tf therapy was shown to be effective in preclinical studies, as the mice showed improved erythropoiesis and anemia (101). Additional studies have shown that the JAK2 inhibitor ruxolitinib can reverse splenomegaly in b-thalassemic mouse models and a Phase II clinical trial has been initiated based on these results (32). Although b-thalassemic patients receiving ruxolitinib showed a reduction of spleen size, overall, there were no changes observed in serum iron, ferritin levels, or pretransfusion hemoglobin levels (160).…”

Section: Iron and Hematopoiesismentioning

confidence: 99%

The Role of Iron in Benign and Malignant Hematopoiesis

Sinha

Reis

Guerra

et al. 2021

Antioxidants & Redox Signaling

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Significance: Iron is an essential element required for sustaining a normal healthy life. However, an excess amount of iron in the bloodstream and tissue generates toxic hydroxyl radicals through Fenton reactions. Henceforth, a balance in iron concentration is extremely important to maintain cellular homeostasis in both normal hematopoiesis and erythropoiesis. Iron deficiency or iron overload can impact hematopoiesis and is associated with many hematological diseases. Recent Advances: The mechanisms of action of key iron regulators such as erythroferrone and the discovery of new drugs, such as ACE-536/luspatercept, are of potential interest to treat hematological disorders, such as b-thalassemia. New therapies targeting inflammation-induced ineffective erythropoiesis are also in progress. Furthermore, emerging evidences support differential interactions between iron and its cellular antioxidant responses of hematopoietic and neighboring stromal cells. Both iron and its systemic regulator, such as hepcidin, play a significant role in regulating erythropoiesis. Critical Issues: Significant pre-clinical studies are on the way and new drugs targeting iron metabolism have been recently approved or are undergoing clinical trials to treat pathological conditions with impaired erythropoiesis such as myelodysplastic syndromes or b-thalassemia. Future Directions: Future studies should explore how iron regulates hematopoiesis in both benign and malignant conditions. Antioxid. Redox Signal. 00, 000-000.

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Short-term administration of JAK2 inhibitors reduces splenomegaly in mouse models of β-thalassemia intermedia and major

Abstract: Short-term administration of JAK2 inhibitors reduces splenomegaly in mouse models of b-thalassemia intermedia and major b-thalassemia is one of the most common congenital red blood cell (RBC) disorders characterized by limited bglobin synthesis and ineffective erythropoiesis.

Cited by 29 publications

References 13 publications

Beta Thalassemia: New Therapeutic Options Beyond Transfusion and Iron Chelation

Beta Thalassemia: New Therapeutic Options Beyond Transfusion and Iron Chelation

Innovative Treatments for Rare Anemias

The Role of Iron in Benign and Malignant Hematopoiesis

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