New Therapeutic Options for the Treatment  of Sickle Cell Disease

Mattè, Alessandro; Zorzi, Francesco; Mazzi, Filippo; Federti, Enrica; Olivieri, Oliviero; Franceschi, Lucia De

doi:10.4084/mjhid.2019.002

Cited by 35 publications

(29 citation statements)

References 142 publications

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“…With growing evidence of the safety and efficacy of hydroxyurea, its use has increased in high- and lower-income countries, but it continues to be underused 7. Alongside hydroxyurea, novel therapeutic agents inducing HbF are currently under investigations 8. The survival of children with SCD approaches that of unaffected children 9.…”

Section: Introductionmentioning

confidence: 99%

Sickle Cell Disease and Infections in High- And Low-Income Countries

Cannas¹

2019

Mediterr J Hematol Infect Dis

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Infections, especially pneumococcal septicemia, meningitis, and Salmonella osteomyelitis, are a major cause of morbidity and mortality in patients with sickle cell disease (SCD). SCD increased susceptibility to infection, while infection leads to SCD-specific pathophysiological changes. The risk of infectious complications is highest in children with a palpable spleen before 6 months of age. Functional splenectomy, the results of repeated splenic infarctions, appears to be an important host-defense defect. Infection is the leading cause of death, particularly in less developed countries. Defective host-defense mechanisms enhance the risk of pneumococcal complications. Susceptibility to Salmonella infections can be explained at least in part by a similar mechanism. In high-income countries, the efficacy of the pneumococcal vaccine has been demonstrated in this disease. A decreased in infection incidence has been noted in SCD patients treated prophylactically with daily oral penicillin. Studies in low-income countries suggest the involvement of a different spectrum of etiological agents.

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Section: Introductionmentioning

confidence: 99%

Sickle Cell Disease and Infections in High- And Low-Income Countries

Cannas¹

2019

Mediterr J Hematol Infect Dis

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“…The dense, rigid red blood cells are easily trapped within organs with sluggish microcirculation by their interaction with the inflammatory activated vascular endothelial cells and neutrophils. These events generate acute vaso-occlusive events, which leads to ischemic-reperfusion damage of target organs such as lung, kidney or brain [3–6].…”

Section: Introductionmentioning

confidence: 99%

Current challenges in the management of patients with sickle cell disease – A report of the Italian experience

Russo

Franceschi

Colombatti

et al. 2019

Orphanet J Rare Dis

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Sickle cell disease (SCD) is an inherited red blood cell disorder caused by a structural abnormality of hemoglobin called sickle hemoglobin (HbS). Clinical manifestations of SCD are mainly characterized by chronic hemolysis and acute vaso-occlusive crisis, which are responsible for severe acute and chronic organ damage. SCD is widespread in sub-Saharan Africa, in the Middle East, Indian subcontinent, and some Mediterranean regions. With voluntary population migrations, people harboring the HbS gene have spread globally. In 2006, the World Health Organization recognized hemoglobinopathies, including SCD, as a global public health problem and urged national health systems worldwide to design and establish programs for the prevention and management of SCD. Herein we describe the historical experience of the network of hemoglobinopathy centers and their approach to SCD in Italy, a country where hemoglobinopathies have a high prevalence and where SCD, associated with different genotypes including ß-thalassemia, is present in the native population.

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“…Crizanlizumab is a monoclonal antibody that targets P-selectin to prevent pathological endothelial adhesion of sickle erythrocytes and leukocytes, leading to a reduction in the frequency of painful (VOCs) (17,18). The anti-sickling agent Voxelotor is the first of a new class of aromatic aldehydes that target HbS polymerization by increasing Hb O 2 affinity (19)(20)(21).…”

Section: Introductionmentioning

confidence: 99%

Sulfated non-anticoagulant heparin derivative modifies intracellular hemoglobin, inhibits cell sickling in vitro, and prolongs survival of sickle cell mice under hypoxia

et al. 2021

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Sickle cell disease (SCD) is an autosomal recessive genetic disease caused by a single point mutation, resulting in abnormal sickle hemoglobin (HbS). During hypoxia or dehydration, HbS polymerizes to form insoluble aggregates and induces sickling of red blood cells (RBCs). RBC sickling increases adhesiveness of RBCs to alter the rheological properties of the blood and triggers inflammatory responses, leading to hemolysis and vaso-occlusive crisis sequelae. Unfractionated heparin (UFH) and low-molecular weight heparins (LMWH) have been suggested as treatments to relieve coagulation complications in SCD. However, they are associated with bleeding complications after repeated dosing. An alternative sulfated nonanticoagulant heparin derivative (S-NACH) was previously reported to have none to low systemic anticoagulant activity and no bleeding side effects, and it interfered with P-selectindependent binding of sickle cells to endothelial cells, with concomitant decrease in the levels of adhesion biomarkers in SCD mice. S-NACH has been further engineered and structurally enhanced to bind with and modify HbS to directly inhibit sickling, thus employing a multimodal approach. Here, we show that S-NACH can (i) directly engage in Schiff-base reactions with HbS to decrease RBC sickling under both normoxia and hypoxia in vitro, ii) prolong the survival of SCD mice under hypoxia, and (iii) regulate the altered steady state levels of pro- and antiinflammatory cytokines. Thus, our proof of concept in vitro and in vivo preclinical studies demonstrate that the multimodal S-NACH is a highly promising candidate for development into an improved and optimized alternative to LMWHs for the treatment of patients with SCD.

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New Therapeutic Options for the Treatment of Sickle Cell Disease

Cited by 35 publications

References 142 publications

Sickle Cell Disease and Infections in High- And Low-Income Countries

Sickle Cell Disease and Infections in High- And Low-Income Countries

Current challenges in the management of patients with sickle cell disease – A report of the Italian experience

Sulfated non-anticoagulant heparin derivative modifies intracellular hemoglobin, inhibits cell sickling in vitro, and prolongs survival of sickle cell mice under hypoxia

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