RoFAR awards another 1.2 million Swiss Francs to fund ground-breaking anemia research in Europe and the USA
In just 18 months, RoFAR has awarded funding to 21 international research projects
RoFAR (The Roche Foundation for Anemia Research) announced today that it has awarded a further 1.2 million Swiss Francs (USD 900 000) to seven new anemia-related research projects proposed by scientists and physicians in Austria, Switzerland, the UK and the USA.
Since it began in 2004 RoFAR has provided essential funding totalling 4.1 million Swiss Francs (USD 3.1 million) to support novel research designed to expand the understanding of anemia in renal disease, cancer, chronic illness and cardiovascular disease and the role of erythropoietin as a neuroprotective agent.
Innovation in anemia research is important because anemia and the physiological process associated with red blood cell formation may impact on the body and therefore the health of patients beyond what is currently understood. For example recent interest has been focused on the complex and little understood relationship that exists between anemia and poor cardiac health in patients with chronic renal illness. Anemia is seen in up to 90% of patients with impaired renal function due to chronic kidney disease and in 60% of patients with cancer.
Announcing the awards, Dr Jim Armitage, member of the RoFAR Board of Trustees and an oncologist at the University of Nebraska Medical Center, USA, said “The depth and breadth of submissions for the RoFAR awards certainly reinforces that research into anemia is robust, and far-reaching and there are very compelling scientific questions that the medical community would like to answer. Our understanding of anemia and its impact on chronic kidney disease, cancer and other illnesses will grow through the work of these inquiring scientists.”
The award winners and their fields of research are:
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Professor Max Gassmann
University of Zurich
Switzerland
The Impact of Erythropoietin on the Hypoxic Ventilatory Response of Mouse and Man |
For decades, the blood hormone erythropoietin (Epo) has been thought to exert solely an erythropoietic function. Within the last few years, we and others discovered that Epo is expressed by neuronal cells, too, and that it has (neuro)protective effects such as protecting the brain from stroke or the retina from degeneration. However, a physiological role for brain-derived Epo has not been established so far. We very recently demonstrated that Epo directly influences the respiratory center via central (brainstem) and peripheral (carotid bodies) organs (Soliz et al., in press). This finding proves that Epo has a crucial role in the acclimatization to reduced environmental oxygen. We propose to extend our studies as follows: A) Considering that women and female mammals demonstrated a better capacity to adapt to hypoxia, we are interested to define as whether gender-specific differences occur in the Epo-enhanced ventilatory response in hypoxia. B) We also plan to investigate as whether Epo increases the carotid body sensitivity to oxygen changes in blood. C) As the data described above has been obtained in mice only, we plan to determine in a first step as whether Epo influences ventilation in man, too. We expect to provide new mechanistical insights in the Epo-mediated ventilatory response to hypoxia that may translate into clinical application involved in ventilatory diseases such as Chronic Mountain Sickness and premature newborn apnoea.
Progress report available: 
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Dr. Peter J Kirkpatrick
University of Cambridge
UK
Effects of systemic erythropoietin therapy on cerebral autoregulation and the incidence of delayed ischemic deficits in patients with aneurysmal subarachnoid haemorrhage
(1-year project) |
Intracranial bleeding from a ruptured cerebral blood vessel (called a subarachnoid haemorrhage) affects 7000 patients each year in the UK and is a source of considerable death and disability, even in young adults. Recent observations indicate that these bleeds can cause narrowing of the brain vessel (vasospasm) leading to reduced blood flow and eventual stroke. In this study we wish to use erythropoietin, a widely used natural human hormone for treating anaemia, to reduce vasospasm and clinical deterioration from low blood flow. A man-made version has shown promise in improving outcome of general stroke patients, and beneficial effects can be seen within a few days of treatment. In this proposal we would like to treat subarachnoid haemorrhage patients with erythropoietin soon after they are admitted to hospital. We will compare these patients with those treated with a dummy drug (placebo). Safety will be scrutinised, and ultrasound used to examine aspects of cerebral blood flow known to influence patient outcome. We also aim to identify any evidence of reduced episodes of neurological worsening in patients given erythropoietin. Results from this study will help in the design of a larger trial needed to examine clinical outcome. Benefits identified may be helpful in other conditions associated with cerebral haemorrhage.
Final report available:
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Dr. Veronique Lefebvre
Cleveland Clinic Foundation
USA
Roles of Sox6 in erythropiesis
| This project is designed to help us better understand how the gene called Sox6 controls formation and function of red blood cells in the mouse under normal and anaemia conditions. Sox6 codes for a protein (a transcription factor) that helps specific types of cells activate the genes that they need to fulfil their specialized functions. We found recently that red cells are among these cell types. Both the overall production and the quality of red cells are affected in mouse foetuses and pups that lack Sox6. Using cellular and molecular approaches, we have found that Sox6 helps red cell precursors proliferate and develop fast and undergo terminal maturation properly. Sox6 is thereby required for optimal function and long-term survival of red cells in the blood stream. Sox6 is made in red cell precursors in response to erythropoietin and thus contributes to mediate the effect of this essential hormone in boosting red cell formation. Our first aim is to continue our studies in the mouse to determine whether Sox6 is also important in red cell formation in childhood and adulthood under normal conditions and to recover quickly from anaemia. Our second aim is to use cellular and molecular assays to identify the specific genes that Sox6 activates and that have major roles in red cell formation. We will particularly ask whether Sox6 helps red blood cells assemble the specialized protein network (cytoskeleton) that critically helps them mature and acquire their specific shape, and thereby fulfil their functions and survive in the circulation. We anticipate that this study will greatly increase our molecular understanding of red cell formation and the roles of Sox6 in this process and in anaemia, and will thereby suggest genetic causes for some types of anaemia diseases and new treatments for various forms of anaemia diseases.
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Professor Stephen L Leib
University of Berne
Switzerland
Effect of erythropoietin on brain injury and regeneration in bacterial meningitis
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Bacterial meningitis is associated with a mortality rate of up to 30% and up to half of survivors suffer from permanent neurological sequelae including deafness and learning impairment. The dramatic mortality and morbidity rates have remained unchanged for several decades in spite of advances in antimicrobial and intensive care therapies.
Injury caused by bacterial meningitis prominently affects the inner ear and two brain structures, namely the cortex and the hippocampus. In the cortex, the damage includes areas of cerebral infarction. A specific form of brain injury, namely apoptosis in the hippocampus has been observed in patients dying from bacterial meningitis. The affected brain structure is responsible for learning and memory functions.
Erythropoietin has been shown to protect the brain from injury by stroke, a disease with similarities to bacterial meningitis. In addition to this protective effect, erythropoietin has been shown to increase brain repair mechanisms.
We thus hypothesize that adjuvant erythropoietin exerts a beneficial effect in bacterial meningitis by the combined effect of preventing acute brain damage and increasing brain repair mechanisms.
In the proposed project we plan to assess in experimental bacterial meningitis (i) whether therapy with erythropoietin prevents acute brain damage; (ii) whether this beneficial effect is still evident when therapy with erythropoietin is delayed until symptomatic disease and started together with antibiotics at 18 hours after infection (reflecting the clinical situation) (iii) whether erythropoietin attenuates injury to the inner ear and thus prevents hearing loss, the most frequent sequel of bacterial meningitis;(iv) whether erythropoietin increases brain repair mechanisms (e.g. expansion of brain stem cells) in the late phase of the disease and; (iv) whether the combined effect of erythropoietin mediated protection and increased brain repair leads to improved outcome assessed by learning and hearing performance in long term survivors of bacterial meningitis.
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Dr. Barbara Scheiber-Mojdehkar
Medical University of Vienna
Austria
Recombinant human erythropoietin: A new treatment for Friedreich`s ataxia
| Friedreich’s ataxia (FRDA) is the most common of the inherited ataxias, affecting one in 50,000 people. FRDA is caused by a GAA-trinucleotide expansion in the frataxin gene, resulting in a reduced expression of frataxin, a small mitochondrial protein. The exact physiological function of frataxin is unknown, but it may be involved in mitochondrial iron homeostasis and/or assembly of iron-sulfur (FeS) proteins and heme synthesis. Clinically there is an intramitochondrial iron accumulation in heart, liver, nervous system and spleen of FRDA-patients, as well as a reduction of mitochondrial DNA, the FeS cluster-containing subunits of the mitochondrial electron transport chain (complex I-III) and of the enzyme aconitase.
We found that additionally to its reported neuro- and cardioprotective properties recombinant human erythropoietin (rhuEPO) significantly increases frataxin expression in primary lymphocytes from FRDA-patients. Additionally rhuEPO can increase frataxin expression in many other cell types among them the most affected in FRDA such as neurons and cardiac cells. The potential therapeutic role of rhuEPO for the treatment of FRDA will be directly tested in an open-label, single-dose pilot study in FRDA-patients. For this study we will recruit 13 FRDA patients where 7 out of 13 have been tested for in vitro response of their lymphocytes to rhuEPO-treatment. We will test if the effects on frataxin expression seen in vitro can also be seen ijn patients. Therefore the safety and efficacy of rhuEPO for the treatment of FRDA will be tested in an open-label, single-dose pilot study.
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Professor Jürg Schifferli
University Hospital Basel
Basel, Switzerland
Erythropoietin or erythrocyte transfusion for anaemia?
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Over years evidence has accumulated suggesting that blood transfusions may be immunosuppressive, favour infections and diminish the survival of patients with severe disease. The mechanisms responsible for this immunosuppression are not well understood. Red blood cells release small vesicles during storage. These vesicles are budding off from the cell surface of red blood cells. They are found in every red blood cell bag, and apparently do no immediate harm when transfused. The aim of the present project is to test the hypothesis that these small vesicles released by red blood cells are immunosuppressive.
This hypothesis is based on the similarities between the structure of vesicles released by red blood cells and white blood cells (polymorphonuclear leucocytes); the latter have been shown to have immunosuppressive properties.
To test our hypothesis, we will perform experiments in the laboratory using vesicles released by human and mouse red blood cells, to see whether they inhibit inflammation and immunity in cell culture models and in mice. The work will require 2 years. The next steps would be to see whether such mice are prone to infections.
An immunosuppressive activity of red blood cell vesicles would evidently mean that transfusion should be avoided whenever possible, and particularly in patients who are already immunosuppressed. The logical consequences would be to explore further the possibility to replace red blood cell transfusion by erythropoietin treatment whenever possible, particularly in chronic diseases.
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Dr. Marcela Votruba
Cardiff University
UK
Erythropoietin neuroprotection in retinal neurodegeneration
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Programmed cell death (apoptosis) is the final common pathway of neural loss in the visual system in a variety of neurodegenerative diseases, some of which are primarily genetic, such as photoreceptor degenerations (retinitis pigmentosa, cone dystrophies and Stargardts macular dystrophy) and retinal ganglion cell (RGC) degenerations (inherited optic neuropathies and glaucoma). We have recently generated a novel model of RGC neurodegeneration, in which the genetic defect is in the murine gene opa1, and leads to a primary retinal ganglion cell loss in postnatal life by a mechanism of apoptosis triggered by mitochondrial dysfunction. The human counterpart of this is the primary inherited optic neuropathy, autosomal dominant optic atrophy (ADOA), caused by mutation in the OPA1 gene. We have also established in vitro model systems using primary retinal ganglion cells, with OPA1 knockdown, in our laboratory.
The identification of the growth and survival factor erythropoietin (EPO) receptor on tissues and cells other than red cell progenitor cells suggests that EPO may have biological roles and functions other than the stimulation of erythropoiesis. Central nervous system (CNS) EPO receptors are expressed on neurons, astrocytes, microglia and myelin sheaths and EPO is thought to have neuroprotective and neurotrophic effects on neuronal cells. The aim of this study is to explore the neuroprotective effect of EPO in neural retina in a model of primary RGC degeneration, using both a whole organism and cells in culture. We suggest that EPO, which is expressed in neural retina and acts at the mitochondrial membrane to protect nerve cells from apoptosis under adverse cellular conditions, can protect against RGC loss triggered by single gene defects in the neural retina. Our models will be used to investigate the effect of EPO administered systemically and locally on retinal ganglion cell loss and retinal degeneration. The end-point will be assessment of retinal morphology, functional vision and cell survival.
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