Rare Anemias: Are Their Names Just Smoke and Mirrors?

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Activation of pyruvate kinase as therapeutic option for rare hemolytic anemias:Shedding new light on an old enzyme

Novel developments in therapies for various hereditary hemolytic anemias reflect the pivotal role of pyruvate kinase (PK), a key enzyme of glycolysis, in red blood cell (RBC) health. Without PK catalyzing one of the final steps of the Embden-Meyerhof pathway, there is no net yield of adenosine triphosphate (ATP) during glycolysis, the sole source of energy production required for proper RBC function and survival. In hereditary hemolytic anemias, RBC health is compromised and therefore lifespan is shortened. Although our knowledge on glycolysis in general and PK function in particular is solid, recent advances in genetic, molecular, biochemical, and metabolic aspects of hereditary anemias have improved our understanding of these diseases. These advances provide a rationale for targeting PK as therapeutic option in hereditary hemolytic anemias other than PK deficiency. This review summarizes the knowledge, rationale, (pre)clinical trials, and future advances of PK activators for this important group of rare diseases.</p

Interplay of erythropoietin, fibroblast growth factor 23, and erythroferrone in patients with hereditary hemolytic anemia

Recently, erythropoietin (EPO) was identified as regulator of fibroblast growth factor 23 (FGF23). Proteolytic cleavage of biologically active intact FGF23 (iFGF23) results in the formation of C-terminal fragments (cFGF23). An increase in cFGF23 relative to iFGF23 suppresses FGF receptor signaling by competitive inhibition. EPO lowers the i:cFGF23 ratio, thereby overcoming iFGF23-mediated suppression of erythropoiesis. We investigated EPO-FGF23 signaling and levels of erythroferrone (ERFE) in 90 patients with hereditary hemolytic anemia (www.trialregister.nl [NL5189]). We show, for the first time, the importance of EPO-FGF23 signaling in hereditary hemolytic anemia: there was a clear correlation between total FGF23 and EPO levels (r = +0.64; 95% confidence interval [CI], 0.09-0.89), which persisted after adjustment for iron load, inflammation, and kidney function. There was no correlation between iFGF23 and EPO. Data are consistent with a low i:cFGF23 ratio. Therefore, as expected, we report a correlation between EPO and ERFE in a diverse set of hereditary hemolytic anemias (r = +0.47; 95% CI, 0.14-0.69). There was no association between ERFE and total FGF23 or iFGF23, which suggests that ERFE does not contribute to the connection between FGF23 and EPO. These findings open a new area of research and might provide potentially new druggable targets with the opportunity to ameliorate ineffective erythropoiesis and the development of disease complications in hereditary hemolytic anemias

The EPO-FGF23 Signaling Pathway in Erythroid Progenitor Cells: Opening a New Area of Research

We provide an overview of the evidence for an erythropoietin-fibroblast growth factor 23 (FGF23) signaling pathway directly influencing erythroid cells in the bone marrow. We outline its importance for red blood cell production, which might add, among others, to the understanding of bone marrow responses to endogenous erythropoietin in rare hereditary anemias. FGF23 is a hormone that is mainly known as the core regulator of phosphate and vitamin D metabolism and it has been recognized as an important regulator of bone mineralization. Osseous tissue has been regarded as the major source of FGF23. Interestingly, erythroid progenitor cells highly express FGF23 protein and carry the FGF receptor. This implies that erythroid progenitor cells could be a prime target in FGF23 biology. FGF23 is formed as an intact, biologically active protein (iFGF23) and proteolytic cleavage results in the formation of the presumed inactive C-terminal tail of FGF23 (cFGF23). FGF23-knockout or injection of an iFGF23 blocking peptide in mice results in increased erythropoiesis, reduced erythroid cell apoptosis and elevated renal and bone marrow erythropoietin mRNA expression with increased levels of circulating erythropoietin. By competitive inhibition, a relative increase in cFGF23 compared to iFGF23 results in reduced FGF23 receptor signaling and mimics the positive effects of FGF23-knockout or iFGF23 blocking peptide. Injection of recombinant erythropoietin increases FGF23 mRNA expression in the bone marrow with a concomitant increase in circulating FGF23 protein. However, erythropoietin also augments iFGF23 cleavage, thereby decreasing the iFGF23 to cFGF23 ratio. Therefore, the net result of erythropoietin is a reduction of iFGF23 to cFGF23 ratio, which inhibits the effects of iFGF23 on erythropoiesis and erythropoietin production. Elucidation of the EPO-FGF23 signaling pathway and its downstream signaling in hereditary anemias with chronic hemolysis or ineffective erythropoiesis adds to the understanding of the pathophysiology of these diseases and its complications; in addition, it provides promising new targets for treatment downstream of erythropoietin in the signaling cascade

Red Blood Cell Membrane Conductance in Hereditary Haemolytic Anaemias

Congenital haemolytic anaemias are inherited disorders caused by red blood cell membrane and cytoskeletal protein defects, deviant hemoglobin synthesis and metabolic enzyme deficiencies. In many cases, although the causing mutation might be known, the pathophysiology and the connection between the particular mutation and the symptoms of the disease are not completely understood. Thus effective treatment is lagging behind. As in many cases abnormal red blood cell cation content and cation leaks go along with the disease, by direct electrophysiological measurements of the general conductance of red blood cells, we aimed to assess if changes in the membrane conductance could be a possible cause. We recorded whole-cell currents from 29 patients with different types of congenital haemolytic anaemias: 14 with hereditary spherocytosis due to mutations in α-spectrin, β-spectrin, ankyrin and band 3 protein; 6 patients with hereditary xerocytosis due to mutations in Piezo1; 6 patients with enzymatic disorders (3 patients with glucose-6-phosphate dehydrogenase deficiency, 1 patient with pyruvate kinase deficiency, 1 patient with glutamate-cysteine ligase deficiency and 1 patient with glutathione reductase deficiency), 1 patient with β-thalassemia and 2 patients, carriers of several mutations and a complex genotype. While the patients with β-thalassemia and metabolic enzyme deficiencies showed no changes in their membrane conductance, the patients with hereditary spherocytosis and hereditary xerocytosis showed largely variable results depending on the underlying mutation

Delivering sustained, coordinated and integrated observations of the Southern Ocean for global impact

The Southern Ocean is disproportionately important in its effect on the Earth system, impacting climatic, biogeochemical, and ecological systems, which makes recent observed changes to this system cause for global concern. The enhanced understanding and improvements in predictive skill needed for understanding and projecting future states of the Southern Ocean require sustained observations. Over the last decade, the Southern Ocean Observing System (SOOS) has established networks for enhancing regional coordination and research community groups to advance development of observing system capabilities. These networks support delivery of the SOOS 20-year vision, which is to develop a circumpolar system that ensures time series of key variables, and delivers the greatest impact from data to all key end-users. Although the Southern Ocean remains one of the least-observed ocean regions, enhanced international coordination and advances in autonomous platforms have resulted in progress toward sustained observations of this region. Since 2009, the Southern Ocean community has deployed over 5700 observational platforms south of 40°S. Large-scale, multi-year or sustained, multidisciplinary efforts have been supported and are now delivering observations of essential variables at space and time scales that enable assessment of changes being observed in Southern Ocean systems. The improved observational coverage, however, is predominantly for the open ocean, encompasses the summer, consists of primarily physical oceanographic variables, and covers surface to 2000 m. Significant gaps remain in observations of the ice-impacted ocean, the sea ice, depths >2000 m, the air-ocean-ice interface, biogeochemical and biological variables, and for seasons other than summer. Addressing these data gaps in a sustained way requires parallel advances in coordination networks, cyberinfrastructure and data management tools, observational platform and sensor technology, two-way platform interrogation and data-transmission technologies, modeling frameworks, intercalibration experiments, and development of internationally agreed sampling standards and requirements of key variables. This paper presents a community statement on the major scientific and observational progress of the last decade, and importantly, an assessment of key priorities for the coming decade, toward achieving the SOOS vision and delivering essential data to all end-users.Fil: Newman, Louise. University of Tasmania; AustraliaFil: Heil, Petra. Australian Antarctic Division; Australia. Antarctic Climate And Ecosystems Cooperative Research Centre; AustraliaFil: Trebilco, Rowan. Australian Antarctic Division; Australia. Antarctic Climate And Ecosystems Cooperative Research Centre; AustraliaFil: Katsumata, Katsuro. Japan Agency For Marine earth Science And Technology; JapónFil: Constable, Andrew J.. Antarctic Climate And Ecosystems Cooperative Research Centre; Australia. Australian Antarctic Division; AustraliaFil: Wijk, Esmee van. Commonwealth Scientific And Industrial Research Organization; Australia. Antarctic Climate And Ecosystems Cooperative Research Centre; AustraliaFil: Assmann, Karen. University Goteborg; SueciaFil: Beja, Joana. British Oceanographic Data Centre; AustraliaFil: Bricher, Phillippa. University of Tasmania; AustraliaFil: Coleman, Richard. University of Tasmania; AustraliaFil: Costa, Daniel. University of California; Estados UnidosFil: Diggs, Steve. University of California; Estados UnidosFil: Farneti, Riccardo. The Abdus Salam; Italia. The Abdus Salam. International Centre for Theoretical Physics; ItaliaFil: Fawcett, Sarah. University of Cape Town; SudáfricaFil: Gille, Sarah. University of California; Estados UnidosFil: Hendry, Katharine R.. University of Bristol; Reino UnidoFil: Henley, Sian F.. University of Edinburgh; Reino UnidoFil: Hofmann, Eileen. Old Dominion University; Estados UnidosFil: Maksym, Ted. University of California; Estados UnidosFil: Mazloff, Matthew. University of California; Estados UnidosFil: Meijers, Andrew J.. British Antartic Survey; Reino UnidoFil: Meredith, Michael. British Antartic Survey; Reino UnidoFil: Moreau, Sebastien. Norwegian Polar Institute; NoruegaFil: Ozsoy, Burcu. Istanbul Teknik Üniversitesi; TurquíaFil: Robertson, Robin. Xiamen University; ChinaFil: Schloss, Irene Ruth. Universidad Nacional de Tierra del Fuego; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Austral de Investigaciones Científicas; ArgentinaFil: Schofield, Oscar. State University of New Jersey; Estados UnidosFil: Shi, Jiuxin. Ocean University Of China; ChinaFil: Sikes, Elisabeth L.. State University of New Jersey; Estados UnidosFil: Smith, Inga J.. University of Otago; Nueva Zeland