Blood · 2013
High-level transgene expression in induced pluripotent stem cell-derived megakaryocytes: correction of Glanzmann thrombasthenia.
СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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Sullivan Spencer K, Mills Jason A, Koukouritaki Sevasti B, Vo Karen K, Lyde Randolph B, Paluru Prasuna, Zhao Guoha, Zhai Li, Sullivan Lisa M, Wang Yuhuan, Kishore Siddharth, Gharaibeh Eyad Z, Lambert Michele P, Wilcox David A, French Deborah L, Poncz Mortimer, Gadue Paul
Аннотация
Megakaryocyte-specific transgene expression in patient-derived induced pluripotent stem cells (iPSCs) offers a new approach to study and potentially treat disorders affecting megakaryocytes and platelets. By using a Gp1ba promoter, we developed a strategy for achieving a high level of protein expression in human megakaryocytes. The feasibility of this approach was demonstrated in iPSCs derived from two patients with Glanzmann thrombasthenia (GT), an inherited platelet disorder caused by mutations in integrin αIIbβ3. Hemizygous insertion of Gp1ba promoter-driven human αIIb complementary DNA into the AAVS1 locus of iPSCs led to high αIIb messenger RNA and protein expression and correction of surface αIIbβ3 in megakaryocytes. Agonist stimulation of these cells displayed recovery of integrin αIIbβ3 activation. Our findings demonstrate a novel approach to studying human megakaryocyte biology as well as functional correction of the GT defect, offering a potential therapeutic strategy for patients with diseases that affect platelet function.