Development of novel therapies for Diamond-Blackfan Anemia

Diamond-Blackfan anemia is a congenital erythroid hypoplasia manifesting early in
life. In at least 60-70% of cases, DBA is caused by a functional haploinsufficiency
of genes encoding for ribosomal proteins. Approximately, 25% percent of patients
have mutations in the gene encoding ribosomal protein S19 (RPS19). The
hematological profile of DBA patients shows macrocytic anemia with
reticulocytopenia, normal or decreased levels of neutrophils and variable platelets
counts. DBA patients also exhibit various non-hematological manifestations such
as physical abnormalities and cancer predisposition. Corticosteroids are the main
therapeutic option in DBA. Around 80% of the patients initially respond to
corticosteroids, but only 40% of patients sustain the therapeutic response and the
remaining 40% of patients need chronic blood transfusion. Twenty% of patients go
into spontaneous remission and maintain an acceptable hemoglobin level without
therapeutic intervention. The only curative treatment available for DBA patients is
allogeneic bone marrow transplantation.
This thesis focuses on understanding the disease pathogenesis and development of
novel therapies for DBA. In Article-I we sought to understand the physiological
relevance of the 5S RNP-Mdm2-p53 pathway for generation of the erythroid defect
upon RPS19 deficiency. In Article-II we aimed to evaluate the therapeutic effect of
the amino acid L-leucine in the treatment of DBA. In Article-III and IV we examine
the feasibility of RPS19 gene therapy in the treatment of RPS19 deficient Diamond
Blackfan Anemia.
In summary, this work focuses on basic and translational research towards
evaluating novel therapies and understanding molecular mechanisms for DBA.