Sickle cell disease of transgenic SAD mice

Abstract

Erythrocyte sickling on deoxygenation in vitro occurs in transgenic SAD mice, hemizygous for a modified human sickle hemoglobin, HbSAD [alpha 2 beta 2S(beta 6val)Antilles (beta 23 lle)D- Punjab (beta 121Gln)] (SAD- 1, 19% HbSAD; beta-thal/SAD-1, 26% HbSAD). The present study examines the cellular defects in vivo and pathologic changes observed in SAD-1 mice at atmospheric oxygenation as well as the effect of acute hypoxia. The transgenic mice showed generalized congestion and microvascular occlusions, occasionally with thrombosis and infarctions of lung, kidneys, penis, and myocardium. The most prevalent chronic organ lesions were congestive splenomegaly (83% of animals) and renal glomerulopathy, which affected 75% of animals by 10 months of age. Further, SAD mice have a mean lifespan that was reduced by 40% when compared with nontransgenic littermates. Premature death of SAD mice was associated with acute vasoocclusive events or severe renal disease. SAD mice developed lethal vasoocclusive processes when exposed to reduced pO2 conditions, whereas control mice survived normally. The sensitivity to hypoxia appears to depend on the cellular level of HbSAD, because death occurred at pO2 of 42 mmHg for SAD mice and 49 mmHg for beta-thal/SAD. Administration of an antisickling agent that increases oxygen affinity (BW12C79) protected SAD and beta-thal/SAD mice from the lethal hypoxic stress. In conclusion, the transgenic SAD and beta-thal/SAD mice developed a pathophysiology that strongly resembles human sickle cell disease. Moreover, this animal model allows studies on the effect of antisickling agents.

Protective effects of phosphodiesterase‐4 (PDE‐4) inhibition in the early phase of pulmonary arterial hypertension in transgenic sickle cell mice

“…In the present study, we analyzed the early phase of pulmonary arterial hypertension in a transgenic sickle cell mouse model (SAD). SAD mice have a relatively mild form of SCD, and they are better suited than other models for the study of lung pathology the development, since they do not normally show severe lung damage (19,48). In SAD mice, prolonged hypoxia (7 days, 8% oxygen) induced pathological lung changes compatible with the early stages of pulmonary arterial hypertension, indicating that the sickle cell SAD hematological phenotype can induce the development of PAH.…”

“…Quantitative data were obtained with PALM robot software version 1.2.1 (PALM.microlaser technologies AG, Bernried, Germany), on an Olympus Provis AX70 microscope with wide-field eyepiece number 26.5 (Olympus, Tokyo, Japan), providing a field size of 0.344 mm 2 at ϫ400. Vascular congestion was evaluated by measuring the percentage of hematoxylin-eosine stained lung sections containing red cells (47,48). The wall thickness of lung arteries was measured on hematoxylin-eosine stained lung sections at ϫ400.…”

Inositol hexaphosphate–loaded red blood cells prevent in vitro sickling

“…The in vivo efficacy of the product must be now demonstrated. So far, IHP was successfully entrapped in murine RBCs and proof of concept in the transgenic mice models of the disease (SAD 25,26 and BERK 27 ) is currently under investigation.…”

Progress Toward the Genetic Treatment of the β‐Thalassemias

“…Because no transgenic mouse model perfectly recapitulates the exact disease characteristics of human SCD patients, Pawliuk et al 73 investigated the efficacy of a lentiviral vector called β87 that closely recapitulates the structure of TNS9. This vector was tested in two different SCD transgenic mouse models: SAD 79 and BERK. 80 Three months after transplantation, mice harbored on average 3 ± 0.5 vector copies in peripheral blood cells.…”