Periodic Reporting for period 1 - InEr-SICKLE (The molecular basis of ineffective erythropoiesis in Sickle Cell Disease)
Okres sprawozdawczy: 2022-02-01 do 2024-01-31
The project relates to Sickle Cell Anemia (SCA), is a genetic disease and one of the most common severe disorders worldwide. The disease is due to a single change in the gene for the oxygen-carrying molecule hemoglobin in red blood cells, which results in the production of faulty hemoglobin and red blood cell deformation resulting in sickling. This in turn results are painful crises where patients experience acute episodes of pain. If left untreated, SCA leads to multiple organ damage and early mortality. SCA is a global health problem, as recognized by the World Health Organization (WHO) in 2008, the United Nations (UN) and the American Society of Hematology (ASH) in 2016. To date, around 300,000 newborns are affected yearly by the disease, and this number is expected to rise to 400,000 by 2050 . The vast majority of affected births occurs in Africa and the Indian subcontinent due to the selection of ickle mutation carriers through their survival advantage in malaria endemic regions. However, due to population movements, SCA has spread worldwide. Recent studies estimate that the overall number of births affected by SCA between 2010 and 2050 to be 14,242,000, with approximately 88% of those in sub-Saharan Africa. Due to a lack of early diagnosis and effective treatments in these countries, 50-90% of the newborns do not survive past the age of 5. Even in developed countries with the best medical care, life expectancy for SCD patients is reduced by about 30 years. Treatment options for SCA remain limited. Bone marrow transplantation and gene therapy offer the only curative approaches, albeit at considerable expense and carrying significant risks associated with transplantation and gene transfer. Blood transfusion is commonly used to treat SCD but has limited efficacy and serious side effects, including iron overload. Regardless of the associated risks or side effects, there are no resources for introducing these treatments in the parts of the world where they are most needed. Whereas several drugs are in the pipeline for development, to-date only one drug (hydroxycarbamide) remains the only widely used drug in the clinic to treat SCA. Therefore, there remains a pressing need to develop new drug-based treatments for SCD that are accessible to patients globally. To achieve this latter objective, the present project focused on understanding the basis for anemia in SCA. It is expected that the new knowledge obtained through these studies will help develop novel, effective and safe therapies that will be accessible in the parts of the world where they are most needed.
As part of the project, we worked with cells from SCA patients and showed that in these cells the process of red blood cell differentiation (i.e. production of red cells from stem cells in the blood) was defective. We showed that patient cells failed to produce red cells in the lab due to high rates of cell death. These observations may explain, in part, the anemia observed in SCA. By exploring the reasons behind the defective red cell differentiation, we showed that the levels of GATA1, a key protein required for red blood cell production, were depleted. Furthermore, we showed that GATA1 depletion is most likely due to the abnormal inflammatory environment in the bone marrow of SCA patients (where red blood cells are produced before being relased in the blood circulation). We were also able to unveil the culprit responsible for GATA1 depletion and, importantly, when the culprit was blocked, GATA1 levels increased and red blood cell differentiation improved. All of this work was also confirmed using a small animal model for SCA.
Work carried out as part of this project provided novel knowledge towards understanding the mechanisms behind anemia in SCA. Furthermore, it uncovered a possible mechanism that may account, in part, for the anemia in SCA and, imporantly, this mehcnaims maybe "druggable" in the development of future therapeutic approaches to alleviate anemia in SCA. This will have singificant impact in the treatment of SCA globally.