The panoply of animal models for sickle cell anaemia

Abstract

A transgenic mouse model expressing exclusively haemoglobin S has been an active objective of sickle cell anaemia research in the last decade because it can: (i) help to understand the pathophysiology of the disease; (ii) help in the development of anti-sickling drugs; and (iii) have potential usefulness for dry runs of anti-sickling gene therapy.Three groups have reported sickle transgenic mouse lines that express only human globin chains Ryan et al, 1997;Chang et al, 1998). This accomplishment required the`knockout' of the murine globin genes, that is, the removal or inactivation of these genes by homologous recombination (Ciavetta et al, 1995;Pa Ászty et al, 1995;Yang et al, 1995;Chang et al, 1998). The strategy used to generate the`knockout' models is described in Fig 1. A better perspective on the characteristics of knockout models with exclusively human globin chains is obtained by first discussing the sickle transgenic models previously available (which are still useful for defined purposes) and contrasting them with the new models.Models with a combination of murine globins and human globin chains The first models expressing moderately high levels of both human a-and b S -globin chains were reported by Greaves et al (1990) and Ryan et al (1990). The former was not propagated and the latter expressed only about 50% b S . Subsequently, many different lines of mice with variable degrees of severity became available allowing more detailed studies of pathology.The SAD-1-mouse. This mouse, generated/characterized by Trudel et al (19911994), expresses the SAD transgene at 19% that contains three mutations (b S , b S±Antilles and b DLos Angeles or b SAD ) in the same b chain (Trudel et al, 1991). The last two mutations enhance polymer formation. When the b major deletion (Skow et al, 1983) is present as the hemizygote (b-thal/SAD or SAD-1/b d3 ), the percentage of b SAD increases to 26% and the phenotype is severe. A human a-globin gene is co-integrated at the same site. This model has been used to test clotrimazol, a Gardos channel blocker that inhibits dense-cell formation and to test Mg 11 supplementation (De Franceschi et al, 1994. The model has provided information on glomerular abnormalities and could be useful for testing therapeutic approaches for priapism. Recently, ineffective erythropoiesis has been demonstrated in SAD and SAD-1/ b d3 mice (Blouin et al, 1999).Blouin et al (2000) have recently described the effect of introducing several levels of human g on the SAD-1 mouse that has no deletions or knockouts. The effect of g on transgenic mouse models is important for both understanding the mechanism of the protective effect of g and as a baseline for evaluating anti-sickling haemoglobins proposed for use in gene therapy. Four different levels of human g were bred into the SAD-1 mouse resulting in mice expressing 5´2, 10´6, 18´4 and 24´4% g as a percentage of all b-like chains; there was a concomitant decrease in the percentage of SAD haemoglobin that was not quantified. The effect of the SAD transgene...

A cure for murine sickle cell disease through stable mixed chimerism and tolerance induction after nonmyeloablative conditioning and major histocompatibility complex–mismatched bone marrow transplantation

“…The recent creation of transgenic mice in which human sickle ␤-globin exists in a background of normal human ␣-globin and a complete knock-out of the endogenous murine ␣-and ␤-globin genes represent the latest advances toward such a model. 16,17,35 These mice recapitulate much of the hematologic pathology seen in human SCD, including hemolytic anemia (with resulting low hemoglobin concentration, low hematocrit, and high reticulocyte count) and high WBC count. Their RBCs do differ from human sickle RBCs in that they have a lower mean corpuscular hemoglobin concentration, likely resulting from a mild ␣/␤ chain imbalance, and subsequent mild thalassemic component to their anemia.…”

“…Their RBCs do differ from human sickle RBCs in that they have a lower mean corpuscular hemoglobin concentration, likely resulting from a mild ␣/␤ chain imbalance, and subsequent mild thalassemic component to their anemia. 16,17,35 It is speculated that this slight ␣/␤ chain imbalance is just enough to prevent this model from being lethal 35 and that the overall authenticity of this model of SCD is not seriously impaired by this difference. 16,17 Importantly, these knock-out models of SCD also show total-body pathology reminiscent of human SCD, including splenic sequestration and enhanced splenic erythropoiesis, renal cortical and glomerular pathology, and liver infarction.…”

Murine glutathione S‐transferase A1‐1 in sickle transgenic mice

“…STM were all on C57 background [18]. All mice were bred and housed in the Animal Facility of the Albert Einstein College of Medicine (AECOM), under guidelines of AAALAC.…”

“…Multiple transgenic mouse models of SCA have been generated and characterized [18]. The S1S-Antilles mice have renal hypertrophy, congested glomeruli, medullary fibrosis, increased GFR, and urine concentrating defect, a phenotype similar to human SCA [19].…”

Intercellular adhesion molecule-4 and CD36 are implicated in the abnormal adhesiveness of sickle cell SAD mouse erythrocytes to endothelium

“…12 Some models, such as the Berkeley mouse, exclusively express human globin chains and exhibit a very severe phenotype entailing a very low percentage of viable pups, very short lifespan, and extreme fragility during manipulation. 13 Other models, such as the SAD mouse, have combined murine and human globin chains.…”