LENTIVIRAL GENE THERAPY RESCUES A NOVEL INDUCIBLE CODANIN-1 KO MOUSE MODEL OF BONE MARROW FAILURE

Congenital Dyserythropoietic Anemia 1 (CDA1) is an inherited blood disorder caused by biallelic mutations in Codanin-1 (Cdan1). Complications from CDA1 are primarily derived from deficient erythropoiesis and include splenomegaly, hemochromatosis, and hyperbilirubinemia, which are further exacerbated by chronic transfusion dependence. Currently, no cure is available, and the lack of a viable CDA1 mouse model has prevented attempts to develop treatments.  We have developed two CDA1 models wherein a floxed Cdan1 allele is excised either by Mx-Cre after induction with a dsRNA analog (Cdan1Mx-cre-KO) or via Cre mRNA containing lipid nanoparticles targeted to hematopoietic stem cells (Cdan1LNP-KO). The fatal phenotype can be reversed by rescuing the model by delivering the human CDAN1 gene via lentiviral gene transfer (AP-CDAN1-FWP). All surviving KO animals show normal erythropoiesis and complete blood counts. Additional studies are underway to analyze lineage-specific hematopoiesis in the bone marrow.  Since hematopoietic stem cells lacking Cdan1 are not viable, we generated mice KO with transgenic Cdan1 using vectors expressing known hypomorphic human CDAN1 mutations. In early studies, and similarly to human CDA1 patients, the mice transduced with mutated CDAN1 alleles exhibit variable decreases in hemoglobin and red blood cell count. In particular, the anemic state is more prominent up to 4 weeks following transplant or a challenge bleed, with CDAN1 mutant mice exhibiting a protracted recovery compared to WT controls. Experiments are underway to characterize erythropoiesis and iron metabolism in these animals. These data indicate that our novel vectors can potentially cure CDA1 and further characterize this disease.