Generation of induced pluripotent stem cells for the cure of ß-thalassemia and sicke cell anemia.
Recent advances in stem cell biology have demonstrated that it is possible to derive induced pluripotent stem cells (iPSC) from thalassemic or SCD human somatic cells. Furthermore, homologous recombination experiments demonstrated that it is possible to correct the mutated ß-globin gene in iPSC cells derived from patients. In other words, it is now possible to reprogram the patient's own blood cells into stem cells and correct their ß-globin gene. The ultimate goal would be to engraft patients with these corrected iPSC-derived bone marrow stem cells and generate healthy red cells. However, generating corrected iPSCs using the current technologies entails several potential drawbacks, including potential disruption of oncogenes and tumor suppressors and further manipulation of the iPSC clones to correct that mutation in the ß-globin gene. Unfortunately that means that we could theoretically cure the SCD and ß-thalassemia but might cause the patients to develop cancer or other diseases. We propose a novel approach to generate corrected iPSCs that overcomes all of these issues. Furthermore, in order to simplify this procedure, we established a protocol to expand blood progenitor cells from a small amount of blood (~30 mL) to generate curative iPSCs.
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Guo S, Casu C, Gardenghi S, Booten S, Watt A, Freier S, Monia BP and Rivella S. "Reducing TMPRSS6 ameliorates hemochromatosis and beta-thalassemia in mice". Journal of Clinical Investigation. 2013 Mar 25.
Casanovas G, Vujiç Spasiç M, Casu C, Rivella S, Strelau J, Unsicker K, Muckenthaler MU. "The murine growth differentiation factor 15 is not essential for systemic iron homeostasis in phlebotomized mice". Haematologica. 2012 Sep 14.
Breda L, Casu C, Gardenghi S, Bianchi N, Cartegni L, Narla M, Yazdanbakhsh K, Musso M, Manwani D, Little J, Gardner LB, Kleinert DA, Prus E, Fibach E, Grady RW, Giardina PJ, Gambari R, Rivella S. "Therapeutic Hemoglobin Levels after Gene Transfer in β-Thalassemia Mice and in Hematopoietic Cells of β-Thalassemia and Sickle Cells Disease Patients". PLoS One. 2012;7(3):e32345.
Parrow NL, Gardenghi S, Ramos P, Casu C, Grady RW, Anderson ER, Shah YM, Li H, Ginzburg YZ, Fleming RE, Rivella S. "Decreased hepcidin expression in murine β-thalassemia is associated with suppression of Bmp/Smad signaling". Blood. 2012 Mar 29;119(13):3187-9.
Kobayashi H, Gilbert V, Liu Q, Kapitsinou PP, Unger TL, Rha J, Rivella S, Schlöndorff D, Haase VH. "Myeloid Cell-Derived Hypoxia-Inducible Factor Attenuates Inflammation in Unilateral Ureteral Obstruction-Induced Kidney Injury". Journal of Immunology. 2012 Apr 6.
Zuccato C, Breda L, Salvatori F, Breveglieri G, Gardenghi S, Bianchi N, Brognara E, Lampronti I, Borgatti M, Rivella S, Gambari R. "A combined approach for β-thalassemia based on gene therapy-mediated adult hemoglobin (HbA) production and fetal hemoglobin (HbF) induction". Ann Hematol. 2012 Mar 31.
Wang L, Rosenberg J, De B, Ferris B, Wang R, Rivella S, Kaminsky S, Crystal R. "In Vivo Gene Transfer Strategies to Achieve Partial Correction of Von Willebrand Disease". Hum Gene Ther. 2012 Apr 6.
Gardenghi S., Ramos P., Marongiu M.F., Melchiori L., Breda L., Guy E., Muirhead K., Rao N., Roy C.N., Andrews N.C., Nemeth E., Follenzi A., An X., Mohandas N., Ginzburg Y., Rachmilewithz E., Giardina P.J., Grady W.R. and Rivella S. "Hepcidin as a therapeutic tool to limit iron overload and improve anemia in beta-thalassemia". Journal of Clinical Investigation. 2010 Dec 1;120(12):4466-77.
Ramos P, Guy E, Gardenghi S, Grady WR, de Sousa M and Rivella S. "Absence of the Hemochromatosis gene HFE in erythroid cells confers protection under condition of stress erythropoiesis and limited iron intake". Blood. Blood. 2010 Nov 8.
Vogiatzi MG., Tsay J., Verdelis K., Rivella S., Grady RW., Doty S., Giardina PJ., Boskey AL. "Changes in bone micro-architecture and biomechanical properties in the th3 thalassemia mouse are associated with decreased bone turnover and occur during the period of bone accrual". Calcified Tissue International. 2010 Jun;86(6):484-94.
Libani IV, Guy E, Melchiori L, Schiro R, Ramos P, Breda L, Scholzen T, Chadburn A, Liu Y, Kernbach M, Baron-Luehr B, Porotto M, de Sousa M, Rachmilewitz E, Hood JD, Domenica Cappellini M, Giardina PJ, Grady RW, Gerdes J and Rivella S. "Decreased differentiation of erythroid cells exacerbates ineffective erythropoiesis in beta-thalassemia". Blood, 2008 Aug 1;112(3):875-85.
Gardenghi S, Marongiu MF, Ramos P, Guy E, Breda L, Chadburn A, Liu Y, Amariglio N, Rechavi G, Rachmilewitz EA, Breuer W, Cabantchik ZI, Wrighting DM, Andrews NC, de Sousa M, Giardina PJ, Grady RW and Rivella S. "Ineffective erythropoiesis in Beta-thalassemia is characterized by increased iron absorption mediated by down-regulation of hepcidin and up-regulation of ferroportin". Blood; 2007 Jun 1; 109(11):5027-35.
Weizer-Stern O, Adamsky K, Amariglio N, Levin C, Koren A, Breuer W, Rachmilewitz E, Breda L, Rivella S, Ioav Cabantchik Z, Rechavi G. "Downregulation of hepcidin and haemojuvelin expression in the hepatocyte cell-line HepG2 induced by thalassaemic sera". British Journal of Haematology; 2006 Oct; 135(1):129-38.