Rescue of Diamond-Blackfan Anemia haploinsufficiency by knock-up of the deficient protein

Diamond-Blackfan Anemia (DBA) is an inherited disease characterised by a defect of red blood cell progenitors within the bone marrow. Usually, the patients show a severe anemia in the first year of life. Approximately 30% of DBA patients have congenital anomalies, including thumb, craniofacial, cardiac and urogenital abnormalities . The treatment includes administration of steroids or chronic blood transfusion, both burdened by severe complications. The only resolutive treatment is stem cell transplantation from a suitable healthy donor. The disease is due to mutations in genes that encode proteins that are necessary to produce ribosomes, the cellular organules that make proteins. A defect in this process cause the death of the red blood cells progenitors and, consequently, the anemia. The objective of this study is to evaluate the efficacy of a new molecular strategy to correct the DBA cell defect. This strategy takes advantage of peculiar RNA molecules, called “non coding antisense RNA SINEUP”. These molecules are not used to produce proteins (they are non-coding RNAs), but they regulate gene expression and the production of other proteins. Some of the researchers that discovered the RNA SINEUPs are part of our research group. We will use these molecules to increase the expression of the deficient protein in cells from patients with DBA and in this way to correct their defect. To evaluate the efficacy of this strategy we will use several cell models, including red blood cell progenitors, obtained from skin or blood cells isolated from the patients and reprogrammed to become progenitors (iPs technology). We will use a specific RNA SINEUP able to increase the amount of the protein that is deficient in the patients. In this way we plan to correct their defect.