Improved Anemia, Organomegaly and Sustained Fetal Hemoglobin Induction within Aging TR2/TR4 Overexpressing UAB Sickle Cell Mice

Abstract Abstract 3248 Background: Fetal Hemoglobin (Hgb F)has been shown to improve morbidity and mortality with SCD patients. We recently published that forced expression of TR2/TR4 resulted in 2.5 fold induction of Fetal Hemoglobin and improved phenotypes within adult 2–3 month humanized sickle cell mice (PNAS Campbell and Cui et al 2011). We wanted to determine the if the Hgb F expression remained durable by HPLC within > 6 m/o mice within SCD:TgTR2/TR4 UAB Mice when compared to 2–3 m/o SCD:TgTR2/TR4 UAB Mice. Further, we wanted to determine if the increased Hgb F expression and improved phenotype observed previously persisted within the 6–8m/o SCD:TgTR2/TR4 mice when compared to the 6–8 m/o SCD UAB Mice. Methods: Humanized Homozygous Knock-In UAB-Sickle Cell (UAB-Hbahα/hα Hbbhβs/hβs) Mice (Wu et al Blood 2006) was mated to TR2/TR4 Overexpressing Mice (TgTR2/TR4) to generate SCD-TR2/TR4 compound heterozygotes (UAB-Hba hα/hα Hbb hβs/hβs TgTR2/TR4). We compared the hemoglobin F levels(HPLC), CBC, and % body weight (liver, spleen, kidney) of 6–8 m/o SCD:TgTR2/TR4(n=5) mice to 2–3 m/o SCD:TgTR2/TR4(n=5) mice. We also analyzed 6–8m/o SCD mice to the TR2/TR4 SCD Mice. Tail PCR genotyping of all SCD Mice were confirmed by HPLC Hemoglobin electrophoresis. Results: Fetal Hemoglobin Expression remained elevated in the 6–8 m/o SCD:TR2/TR4 Mice at 16.7% (+/− 3.94) compared to 18.5% (+/−2.91) in 2–3 month old SCD:TR2/TR4 mice. %BW of spleen (3.7% vs 3.4%) liver (7.29% v 7.8%), kidney (0.98% vs 1.1%), remained similarly lower in the 6–8 m/o compared to the 2–3 m/o mice of the SCD:TR2/TR4 Mice. Table 1 shows increased Hgb F and overall improved anemia and %BW of organs within the older SCD:TR2/TR4 SCD Mice. Conclusions: TR2/TR4 overexpression within >6 m/o humanized SS mouse model resulted in continued >3 fold induction of fetal hemoglobin based on HPLC compared control 6–8 m/o SCD Mice. Further, increased TR2/TR4 overexpression improved anemia, organomegaly, within sickle cell disease mice. Expression of Fetal Hemoglobin by TR2/TR4 remains sustained within older sickle cell mice with improved organomegaly with reversion phenotypically to the wild type phenotype. Disclosures: No relevant conflicts of interest to declare.