Department of Microbiology and Immunology, Temple University School of Medicine, Philadelphia, PA, USA.
Gene Ther. 2011 Feb;18(2):117-27. doi: 10.1038/gt.2010.138. Epub 2010 Oct 21.
After more than 1500 gene therapy clinical trials in the past two decades, the overall conclusion is that for gene therapy (GT) to be successful, the vector systems must still be improved in terms of delivery, expression and safety. The recent development of more efficient and stable vector systems has created great expectations for the future of GT. Impressive results were obtained in three primary immunodeficiencies and other inherited diseases such as congenital blindness, adrenoleukodystrophy or junctional epidermolysis bullosa. However, the development of leukemia in five children included in the GT clinical trials for X-linked severe combined immunodeficiency and the silencing of the therapeutic gene in the chronic granulomatous disease clearly showed the importance of improving safety and efficiency. In this review, we focus on the main strategies available to achieve physiological or tissue-specific expression of therapeutic transgenes and discuss the importance of controlling transgene expression to improve safety. We propose that tissue-specific and/or physiological viral vectors offer the best balance between efficiency and safety and will be the tools of choice for future clinical trials in GT of inherited diseases.
在过去的二十年中，经过超过 1500 项基因治疗临床试验，总的结论是，为了使基因治疗（GT）取得成功，载体系统在输送、表达和安全性方面仍需改进。最近更高效和稳定的载体系统的发展为 GT 的未来带来了巨大的期望。在三种原发性免疫缺陷病和其他遗传性疾病（如先天性失明、肾上腺脑白质营养不良或交界性大疱性表皮松解症）中取得了令人印象深刻的结果。然而，在 X 连锁严重联合免疫缺陷症的 GT 临床试验中包括的五名儿童中出现白血病，以及慢性肉芽肿病中治疗基因的沉默，清楚地表明了提高安全性和效率的重要性。在这篇综述中，我们重点讨论了实现治疗性转基因生理或组织特异性表达的主要策略，并讨论了控制转基因表达以提高安全性的重要性。我们提出，组织特异性和/或生理性病毒载体在效率和安全性之间提供了最佳平衡，将成为未来遗传性疾病 GT 临床试验的首选工具。
