Hierarchical scaffold design for mesenchymal stem cell-based gene therapy of hemophilia B

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• 作者：Daniel L. Coutu ; Jessica Cuerquis ; Rouwayda El Ayoubi ; Kathy-Ann Forner ; Ranjan Roy ; Moï ; ra Franç ; ois ; May Griffith ; David Lillicrap ; Azizeh-Mitra Yousefi ; Mark D. Blostein ; Jacques Galipeau
• 关键词：Mesenchymal stem cells ; Gene therapy ; Hemophilia ; Biomineralization ; Self-renewal ; Osteogenesis
• 刊名：Biomaterials
• 出版年：2011
• 出版时间：January 2011
• 年：2011
• 卷：32
• 期：1
• 页码：295-305
• 全文大小：3180 K

文摘

Gene therapy for hemophilia B and other hereditary plasma protein deficiencies showed great promise in pre-clinical and early clinical trials. However, safety concerns about in vivo delivery of viral vectors and poor post-transplant survival of ex vivo modified cells remain key hurdles for clinical translation of gene therapy. We here describe a 3D scaffold system based on porous hydroxyapatite–PLGA composites coated with biomineralized collagen 1. When combined with autologous gene-engineered factor IX (hFIX) positive mesenchymal stem cells (MSCs) and implanted in hemophilic mice, these scaffolds supported long-term engraftment and systemic protein delivery by MSCs in vivo. Optimization of the scaffolds at the macro-, micro- and nanoscales provided efficient cell delivery capacity, MSC self-renewal and osteogenesis respectively, concurrent with sustained delivery of hFIX. In conclusion, the use of gene-enhanced MSC-seeded scaffolds may be of practical use for treatment of hemophilia B and other plasma protein deficiencies.