Therapeutic Hemoglobin Levels after Gene Transfer in β-Thalassemia Mice and in Hematopoietic Cells of β-Thalassemia and Sickle Cells Disease Patients

Preclinical and clinical studies demonstrate the feasibility of treating β-thalassemia and Sickle Cell Disease (SCD) by lentiviral-mediated transfer of the human β-globin gene. However, previous studies have not addressed whether the ability of lentiviral vectors to increase hemoglobin synthesis might vary in different patients

EHA Research Roadmap on Hemoglobinopathies and Thalassemia: An Update

The inherited disorders of hemoglobin, which include sickle cell disease and thalassemias, are the most common and widespread distributed monogenic disorders. Due to a selective advantage in malaria regions, these hemoglobin defects are particularly frequent in Africa, Asia, or in the Mediterranean areas, where malaria was endemic until the last century. In recent decades, the globalization of migration has contributed to generate multiethnic European societies. Due to migration from countries or regions with high hemoglobinopathy frequencies such as Africa, Middle East, or Asia, large numbers of patients with these disorders are living in almost every European country today. Furthermore, the numbers are increasing because of increasing refugee flows toward Europe. Additional requirements are the development of European recommendations and guidelines for diagnosis and effective therapeutic approaches. These, together with the advancement of clinical trials using new drugs and therapeutic procedures could ameliorate the quality of life of patients affected with these diseases and increase their life expectancy. Lastly, coordinated efforts should be made to develop diagnostic pathways for thalassemias and hemoglobinopathies, in order to plan interventions, including prenatal diagnosis and cure. For these reasons, the development of new tools to reliably diagnose anemias is urgently needed and fits well with the needs of personalized medicine. In the last 15 years, hematology research has made many big leaps forward. Our general aim will be to solve several hematologic problems using these new approaches. We expect that the development of such a diagnostic tool will improve timely diagnosis throughout Europe, especially in those countries where it is difficult to gain access to "classical" diagnostic tests

Executive functions in children with specific learning disorders: Shedding light on a complex profile through teleassessment

Executive Functions (EFs) are high-order cognitive processes relevant to learning and adaptation and frequently impaired in children with specific learning disorders (SLDs). This study aimed to investigate EFs in children with SLD and explore the role of specific EF-related subprocesses, such as stimuli processing and processing speed. Fifty-seven SLD and 114 typically developing (TD) children, matched for gender and age, completed four tasks measuring response inhibition, interference control, shifting, and updating on a web-based teleassessment platform. The results show that SLD children performed lower in all EF tasks than TD children, regardless of stimulus type and condition. Mediation analyses suggested that differences between the SLD and TD groups are mediated by EF-related subprocesses, offering an interpretative model of EF deficits in children with SLD

HMGB1 mediates anemia of inflammation in murine sepsis survivors

Patients surviving sepsis develop anemia but the molecular mechanism is unknown. Here we observed that mice surviving polymicrobial Gram-negative sepsis develop hypochromic, microcytic anemia with reticulocytosis. The bone marrow of sepsis survivors accumulates polychromatophilic and orthochromatic erythroblasts. Compensatory extramedullary erythropoiesis in the spleen is defective during terminal differentiation. Circulating TNF and IL-6 are elevated for five days after the onset of sepsis, and serum HMGB1 levels are increased from day seven until at least day 28. Administration of recombinant HMGB1 to healthy mice mediates anemia with extramedullary erythropoiesis and significantly elevated reticulocyte counts. Moreover, administration of anti-HMGB1 monoclonal antibodies after sepsis significantly ameliorates the development of anemia (hematocrit 48.5+/-9.0% versus 37.4+/-6.1%,

2'-O-methoxyethyl splice-switching oligos correct splicing from IVS2-745 β-thalassemia patient cells restoring HbA production and chain rebalance

\u3b2-thalassemia is a disorder caused by altered hemoglobin protein synthesis and affects individuals worldwide. Severe forms of the disease, left untreated, can result in death before the age of 3 years (1). The standard of care consists of chronic and costly palliative treatment by blood transfusion combined with iron chelation. This dual approach suppresses anemia and reduces iron-related toxicities in patients. Allogeneic bone marrow transplant is an option, but limited by the availability of a highly compatible HSC donor. While gene therapy is been explored in several trials, its use is highly limited to developed regions with centers of excellence and well-established healthcare systems (2). Hence, there remains a tremendous unmet medical need to develop alternative treatment strategies for \u3b2-thalassemia (3). Occurrence of aberrant splicing is one of the processes that affects \u3b2-globin synthesis in \u3b2-thalassemia. The (C>G) IVS-2-745 is a splicing mutation within intron 2 of the \u3b2-globin gene. It leads to an aberrantly spliced mRNA that incorporates an intron fragment. This results in an in-frame premature termination codon that inhibits \u3b2-globin production. Here, we propose the use of uniform 2'-O-methoxyethyl (2'-MOE) splice switching oligos (SSOs) to reverse this aberrant splicing in the pre-mRNA. With these lead SSOs we show aberrant to wild type splice switching. This switching leads to an increase of adult hemoglobin (HbA) up to 80% in erythroid cells from patients with the IVS-2-745 mutation. Furthermore, we demonstrate a restoration of the balance between \u3b2-like- and \u3b1-globin chains, and up to an 87% reduction in toxic \u3b1-heme aggregates. While examining the potential benefit of 2'-MOE-SSOs in a mixed sickle-thalassemic phenotypic setting, we found reduced HbS synthesis and sickle cell formation due to HbA induction. In summary, 2'-MOE-SSOs are a promising therapy for forms of \u3b2-thalassemia caused by mutations leading to aberrant splicing

The EHA research roadmap: anemias

In 2016, the European Hematology Association (EHA) published the EHA Roadmap for European Hematology Research1 aiming to highlight achievements in the diagnostics and treatment of blood disorders, and to better inform European policy makers and other stakeholders about the urgent clinical and scientific needs and priorities in the field of hematology. Each section was coordinated by one to two section editors who were leading international experts in the field. In the five years that have followed, advances in the field of hematology have been plentiful. As such, EHA is pleased to present an updated Research Roadmap, now including eleven sections, each of which will be published separately. The updated EHA Research Roadmap identifies the most urgent priorities in hematology research and clinical science, therefore supporting a more informed, focused, and ideally a more funded future for European hematology research. The eleven EHA Research Roadmap sections include Normal Hematopoiesis; Malignant Lymphoid Diseases; Malignant Myeloid Diseases; Anemias and Related Diseases; Platelet Disorders; Blood Coagulation and Hemostatic Disorders; Transfusion Medicine; Infections in Hematology; Hematopoietic Stem Cell Transplantation; CAR-T and Other Cellbased Immune Therapies; and Gene Therap

Cranberry A-type proanthocyanidins selectively target acute myeloid leukemia cells

Most elderly patients affected with acute myeloid leukemia (AML) will relapse and die of their disease even after achieving complete remission, thus emphasizing the urgent need for new therapeutic approaches with minimum toxicity to normal hematopoietic cells. Cranberry (Vaccinium spp.) extracts have exhibited anticancer and chemopreventive properties that have been mostly attributed to A-type proanthocyanidin (A-PAC) compounds. A-PACs, isolated from a commercially available cranberry extract, were evaluated for their effects on leukemia cell lines, primary AML samples, and normal CD34+ cord blood specimens. Our results indicated potent and specific antileukemia activity in vitro. In addition, the antileukemia activity of A-PACs extended to malignant progenitor and stem cell populations, sparing their normal counterparts. The antileukemia effects of A-PACs were also observed in vivo using patient derived xenografts. Surprisingly, we found that the mechanism of cell death was driven by activation of NF-κB. Overall, our data suggest that A-PACs could be used to improve treatments for AML by targeting leukemia stem cells through a potentially novel pathway

The European Hematology Association Roadmap for European Hematology Research. A Consensus Document

Abstract The European Hematology Association (EHA) Roadmap for European Hematology Research highlights major achievements in diagnosis and treatment of blood disorders and identifies the greatest unmet clinical and scientific needs in those areas to enable better funded, more focused European hematology research. Initiated by the EHA, around 300 experts contributed to the consensus document, which will help European policy makers, research funders, research organizations, researchers, and patient groups make better informed decisions on hematology research. It also aims to raise public awareness of the burden of blood disorders on European society, which purely in economic terms is estimated at Euro 23 billion per year, a level of cost that is not matched in current European hematology research funding. In recent decades, hematology research has improved our fundamental understanding of the biology of blood disorders, and has improved diagnostics and treatments, sometimes in revolutionary ways. This progress highlights the potential of focused basic research programs such as this EHA Roadmap. The EHA Roadmap identifies nine sections in hematology: normal hematopoiesis, malignant lymphoid and myeloid diseases, anemias and related diseases, platelet disorders, blood coagulation and hemostatic disorders, transfusion medicine, infections in hematology, and hematopoietic stem cell transplantation. These sections span 60 smaller groups of diseases or disorders. The EHA Roadmap identifies priorities and needs across the field of hematology, including those to develop targeted therapies based on genomic profiling and chemical biology, to eradicate minimal residual malignant disease, and to develop cellular immunotherapies, combination treatments, gene therapies, hematopoietic stem cell treatments, and treatments that are better tolerated by elderly patients. Received December 15, 2015. Accepted January 27, 2016. Copyright © 2016, Ferrata Storti Foundatio

The European Hematology Association Roadmap for European Hematology Research: a consensus document

The European Hematology Association (EHA) Roadmap for European Hematology Research highlights major achievements in diagnosis and treatment of blood disorders and identifies the greatest unmet clinical and scientific needs in those areas to enable better funded, more focused European hematology research. Initiated by the EHA, around 300 experts contributed to the consensus document, which will help European policy makers, research funders, research organizations, researchers, and patient groups make better informed decisions on hematology research. It also aims to raise public awareness of the burden of blood disorders on European society, which purely in economic terms is estimated at €23 billion per year, a level of cost that is not matched in current European hematology research funding. In recent decades, hematology research has improved our fundamental understanding of the biology of blood disorders, and has improved diagnostics and treatments, sometimes in revolutionary ways. This progress highlights the potential of focused basic research programs such as this EHA Roadmap. The EHA Roadmap identifies nine ‘sections’ in hematology: normal hematopoiesis, malignant lymphoid and myeloid diseases, anemias and related diseases, platelet disorders, blood coagulation and hemostatic disorders, transfusion medicine, infections in hematology, and hematopoietic stem cell transplantation. These sections span 60 smaller groups of diseases or disorders. The EHA Roadmap identifies priorities and needs across the field of hematology, including those to develop targeted therapies based on genomic profiling and chemical biology, to eradicate minimal residual malignant disease, and to develop cellular immunotherapies, combination treatments, gene therapies, hematopoietic stem cell treatments, and treatments that are better tolerated by elderly patients