Development of novel therapies for Diamond-Blackfan Anemia

• Diamond-Blackfan anemia is a congenital erythroid hypoplasia manifesting early inlife. In at least 60-70% of cases, DBA is caused by a functional haploinsufficiencyof genes encoding for ribosomal proteins. Approximately, 25% percent of patientshave mutations in the gene encoding ribosomal protein S19 (RPS19). Thehematological profile of DBA patients shows macrocytic anemia withreticulocytopenia, normal or decreased levels of neutrophils and variable plateletscounts. DBA patients also exhibit various non-hematological manifestations suchas physical abnormalities and cancer predisposition. Corticosteroids are the maintherapeutic option in DBA. Around 80% of the patients initially respond tocorticosteroids, but only 40% of patients sustain the therapeutic response and theremaining 40% of patients need chronic blood transfusion. Twenty% of patients gointo spontaneous remission and maintain an acceptable hemoglobin level withouttherapeutic intervention. The only curative treatment available for DBA patients isallogeneic bone marrow transplantation.This thesis focuses on understanding the disease pathogenesis and development ofnovel therapies for DBA. In Article-I we sought to understand the physiologicalrelevance of the 5S RNP-Mdm2-p53 pathway for generation of the erythroid defectupon RPS19 deficiency. In Article-II we aimed to evaluate the therapeutic effect ofthe amino acid L-leucine in the treatment of DBA. In Article-III and IV we examinethe feasibility of RPS19 gene therapy in the treatment of RPS19 deficient DiamondBlackfan Anemia.In summary, this work focuses on basic and translational research towardsevaluating novel therapies and understanding molecular mechanisms for DBA.

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