Departments of Surgery and Immunology, University of Pittsburgh Cancer Institute, University of Pittsburgh, Hillman Cancer Center, 5117 Centre Avenue, Pittsburgh, PA 15213, USA.
Expert Rev Mol Med. 2010 Jan 12;12:e2. doi: 10.1017/S1462399409001331.
The ability to externally regulate the expression or function of a gene product has proven to be a powerful tool in the study of proteins and disease in vitro, and more recently in transgenic animal models. The transfer of these technologies to regulate a therapeutic, adoptively transferred gene product in a clinical setting may provide a means to exert additional control over a large variety of therapies for many diseases, leading to increased safety and effectiveness. This could be applied to any biological therapy, including gene therapy, viral therapies, cellular therapies (such as immune cell therapies, stem cell therapies and bone marrow transplant), some vaccines and even organ transplant. A variety of systems have been used in a basic research setting to conditionally regulate the function of a protein, including control of transcription and mRNA stability, and the use of protein inhibitors. However, most of these have disadvantages for medical use, where a simple, specific, tunable, reversible and broadly applicable means to regulate protein function is needed. Recent advances in controlling the stability or function of proteins through the interaction of small-molecule effectors and fusion domains on the protein have raised the possibility that direct and highly specific external control of therapeutic protein function in humans will be feasible.
事实证明，在外源性调节基因产物的表达或功能方面，这一技术已经成为体外研究蛋白质和疾病的有力工具，并且最近在转基因动物模型中也得到了应用。将这些技术应用于调节临床治疗中经过转导的治疗性基因产物，可能为许多疾病的各种治疗方法提供额外的控制手段，从而提高安全性和有效性。这可以应用于任何生物疗法，包括基因疗法、病毒疗法、细胞疗法（如免疫细胞疗法、干细胞疗法和骨髓移植）、一些疫苗，甚至器官移植。在基础研究环境中，已经使用了多种系统来有条件地调节蛋白质的功能，包括转录和 mRNA 稳定性的控制，以及使用蛋白质抑制剂。然而，这些系统中的大多数都不适合医疗用途，因为医疗用途需要一种简单、特异、可调、可逆且广泛适用的调节蛋白质功能的方法。通过小分子效应物和融合结构域与蛋白质相互作用来控制蛋白质稳定性或功能方面的最新进展，使得直接、高度特异性地调节人类治疗性蛋白功能成为可能。
