ABSTRACTLENTIVIRAL GENE THERAPY PROVIDES ROBUST PROTECTION AGAINST PANCYTOPENIA IN AN INDUCIBLE CODANIN-1 KNOCKOUT MOUSE MODEL Perry Demsko Stefano Rivella The Congenital Dyserythropoietic Anemias (CDAs) are a diverse group of rare heritable blood disorders characterized by anomalies in erythroid maturation and red blood cell production. Mechanistically varied, CDAs have lacked suitable animal models which has inhibited development of tractable therapies. CDA1a is a macrocytic CDA caused by biallelic hypofunctional mutations in Codanin-1, an enigmatic protein whose precise function has not been conclusively established. CDA1a causes morbidity and mortality though moderate to severe anemia and concurrent iron overload. We sought to rectify the lack of animal model by producing a suitable inducible Codanin-1 knockout mouse line with two disparate mechanisms of cre-based deletion, allowing for assessment of treatments for CDA1a. Using our model, we found that deletion of Codanin-1 is incompatible with life with death invariably resulting upon induction. Seeking to take advantage of this opportunity we utilized lentiviral gene therapy to restore Codanin-1 functionality, thereby establishing the ability to use gene therapy to correct CDA1a. Using our model and lentiviral system, we sought to explore human Conanin-1 mutations for better understanding of the disease pathology of CDA1a. We found that human Codanin-1 mutations do not cause disease in mice, allowing us to hypothesize about fundamental differences between human and mouse erythropoiesis. Finally, we deployed machine learning to interrogate in silico the functionality of Codanin-1 and uncovered a putative disease mechanism