Differentiation and Cytometry Unit, Hematopoiesis and Gene Therapy Division, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT), 28040 Madrid, Spain.
Hum Gene Ther. 2013 Jun;24(6):571-83. doi: 10.1089/hum.2012.251.
Advances in cell and gene therapy are opening up new avenues for regenerative medicine. Because of their acquired pluripotency, human induced pluripotent stem cells (hiPSCs) are a promising source of autologous cells for regenerative medicine. They show unlimited self-renewal while retaining the ability, in principle, to differentiate into any cell type of the human body. Since Yamanaka and colleagues first reported the generation of hiPSCs in 2007, significant efforts have been made to understand the reprogramming process and to generate hiPSCs with potential for clinical use. On the other hand, the development of gene-editing platforms to increase homologous recombination efficiency, namely DNA nucleases (zinc finger nucleases, TAL effector nucleases, and meganucleases), is making the application of locus-specific gene therapy in human cells an achievable goal. The generation of patient-specific hiPSC, together with gene correction by homologous recombination, will potentially allow for their clinical application in the near future. In fact, reports have shown targeted gene correction through DNA-Nucleases in patient-specific hiPSCs. Various technologies have been described to reprogram patient cells and to correct these patient hiPSCs. However, no approach has been clearly more efficient and safer than the others. In addition, there are still significant challenges for the clinical application of these technologies, such as inefficient differentiation protocols, genetic instability resulting from the reprogramming process and hiPSC culture itself, the efficacy and specificity of the engineered DNA nucleases, and the overall homologous recombination efficiency. To summarize advances in the generation of gene corrected patient-specific hiPSCs, this review focuses on the available technological platforms, including their strengths and limitations regarding future therapeutic use of gene-corrected hiPSCs.
细胞和基因治疗的进展为再生医学开辟了新的途径。由于其获得的多能性，人类诱导多能干细胞（hiPSC）是再生医学中自体细胞的有前途的来源。它们具有无限的自我更新能力，同时原则上保留分化为人体任何细胞类型的能力。自从 Yamanaka 和同事于 2007 年首次报道 hiPSC 的产生以来，人们已经做出了巨大的努力来理解重编程过程，并生成具有临床应用潜力的 hiPSC。另一方面，基因编辑平台的发展提高了同源重组效率，即 DNA 核酸酶（锌指核酸酶、TAL 效应核酸酶和巨型核酸酶），使得在人类细胞中应用基因特异性基因治疗成为可能。患者特异性 hiPSC 的产生，加上同源重组的基因纠正，将有可能在不久的将来实现其临床应用。事实上，已有报道表明通过 DNA-Nucleases 在患者特异性 hiPSC 中进行靶向基因纠正。已经描述了各种技术来重编程患者细胞并纠正这些患者 hiPSC。然而，没有一种方法比其他方法更有效和更安全。此外，这些技术的临床应用仍然存在重大挑战，例如分化方案效率低下、重编程过程和 hiPSC 培养本身引起的遗传不稳定性、工程化 DNA 核酸酶的功效和特异性以及总体同源重组效率。为了总结基因纠正的患者特异性 hiPSC 的生成进展，本综述重点介绍了现有的技术平台，包括它们在基因纠正的 hiPSC 的未来治疗用途方面的优缺点。
