Bitopertin, a selective oral GLYT1 inhibitor, improves anemia in a mouse model of β-thalassemia

Federti, Enrica; Winter, Michael; Koerner, Annette; Harmeier, Anja; Mazer, Norman A.; Tomka, Tomas; Paolo, Maria Luisa Di; Falco, Luigia De; Andolfo, Immacolata; Beneduce, Elisabetta; Iolascon, Achille; Macias-Garcia, Alejandra; Chen, Jane-Jane; Janin, Anne; Lebouef, Christhophe; Turrini, Franco; Brugnara, Carlo; Franceschi, Lucia De

doi:10.1172/jci.insight.130111

Cited by 25 publications

(35 citation statements)

References 63 publications

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“…Hematologic parameters and red cell indices were evaluated on a Siemens ADVIA 2120 hematology analyzer. Hematocrit and hemoglobin were manually determined [ 27 , 43 , 44 ]. Acanthocyte evaluation and counting were performed on McGrawald-Giemsa-stained blood smears and by electron microscopy [ 42 ].…”

Section: Methodsmentioning

confidence: 99%

Therapeutic targeting of Lyn kinase to treat chorea-acanthocytosis

Peikert

Federti

Constantin

et al. 2021

acta neuropathol commun

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Chorea-Acanthocytosis (ChAc) is a devastating, little understood, and currently untreatable neurodegenerative disease caused by VPS13A mutations. Based on our recent demonstration that accumulation of activated Lyn tyrosine kinase is a key pathophysiological event in human ChAc cells, we took advantage of Vps13a−/− mice, which phenocopied human ChAc. Using proteomic approach, we found accumulation of active Lyn, γ-synuclein and phospho-tau proteins in Vps13a−/− basal ganglia secondary to impaired autophagy leading to neuroinflammation. Mice double knockout Vps13a−/− Lyn−/− showed normalization of red cell morphology and improvement of autophagy in basal ganglia. We then in vivo tested pharmacologic inhibitors of Lyn: dasatinib and nilotinib. Dasatinib failed to cross the mouse brain blood barrier (BBB), but the more specific Lyn kinase inhibitor nilotinib, crosses the BBB. Nilotinib ameliorates both Vps13a−/− hematological and neurological phenotypes, improving autophagy and preventing neuroinflammation. Our data support the proposal to repurpose nilotinib as new therapeutic option for ChAc patients.

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Section: Methodsmentioning

confidence: 99%

Therapeutic targeting of Lyn kinase to treat chorea-acanthocytosis

Peikert

Federti

Constantin

et al. 2021

acta neuropathol commun

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“…This process results in massive production of ROS with severe cellular oxidative damage, leading to a block in cell maturation, increased apoptosis, and ineffective erythropoiesis. In addition, increased ROS in maturing reticulocytes and erythrocytes cause hemolysis and shorten red cell survival in the peripheral circulation (4,5).…”

Section: Introductionmentioning

confidence: 99%

The pyruvate kinase activator mitapivat reduces hemolysis and improves anemia in a β-thalassemia mouse model

Mattè¹,

Federti²,

Kung³

et al. 2021

Journal of Clinical Investigation

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“…Another possible strategy to limit oxidation in pathologic erythropoiesis is to reduce the free pathologic heme. In β-thalassemic mice, we recently reported that bitopertin, a specific glycine transport inhibitor, ameliorates murine β-thalassemic erythropoiesis with the activation of autophagy and improvement of quality control processes during β-thalassemic erythropoiesis [34]. Taken together these data support the importance of modulation/potentiation of an endogenous antioxidant system as a novel therapeutic strategy against severe/prolonged oxidation in normal and pathologic erythropoiesis.…”

Section: Antioxidant System(s) and Stress Erythropoiesismentioning

confidence: 56%

“…Erythroid differentiation is associated with the production of ROS both in response to the EPO cascade and to the presence of free iron required for the biosynthesis of heme [34,[82][83][84]. Previous studies have reported that oxidation activates both Akt and Fyn, thus involving ROS in modulation of signaling pathways during erythropoiesis [11,35,85].…”

Section: Erythropoiesis: the Interplay Between Oxidation And Signal Tmentioning

confidence: 99%

“…Previous studies have shown that chronic and severe oxidative stress plays a crucial role in the pathogenesis of anemia of β-thalassemia [32,33]. This is mainly related to the erythroid accumulation of free α-globin chains and free heme, associated with a perturbation of iron homeostasis [34,35]. SCD is one of the most common monogenic red cell disorders.…”

Section: Introductionmentioning

confidence: 99%

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Oxidation Impacts the Intracellular Signaling Machinery in Hematological Disorders

et al. 2020

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The dynamic coordination between kinases and phosphatases is crucial for cell homeostasis, in response to different stresses. The functional connection between oxidation and the intracellular signaling machinery still remains to be investigated. In the last decade, several studies have highlighted the role of reactive oxygen species (ROS) as modulators directly targeting kinases, phosphatases, and downstream modulators, or indirectly acting on cysteine residues on kinases/phosphatases resulting in protein conformational changes with modulation of intracellular signaling pathway(s). Translational studies have revealed the important link between oxidation and signal transduction pathways in hematological disorders. The intricate nature of intracellular signal transduction mechanisms, based on the generation of complex networks of different types of signaling proteins, revealed the novel and important role of phosphatases together with kinases in disease mechanisms. Thus, therapeutic approaches to abnormal signal transduction pathways should consider either inhibition of overactivated/accumulated kinases or homeostatic signaling resetting through the activation of phosphatases. This review discusses the progress in the knowledge of the interplay between oxidation and cell signaling, involving phosphatase/kinase systems in models of globally distributed hematological disorders.

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Bitopertin, a selective oral GLYT1 inhibitor, improves anemia in a mouse model of β-thalassemia

Cited by 25 publications

References 63 publications

Therapeutic targeting of Lyn kinase to treat chorea-acanthocytosis

Therapeutic targeting of Lyn kinase to treat chorea-acanthocytosis

The pyruvate kinase activator mitapivat reduces hemolysis and improves anemia in a β-thalassemia mouse model

Oxidation Impacts the Intracellular Signaling Machinery in Hematological Disorders

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