Brown Nolan, Song Liujiang, Kollu Nageswara R, Hirsch Matthew L
1 Gene Therapy Center, University of North Carolina at Chapel Hill , North Carolina.
2 Department of Ophthalmology, University of North Carolina at Chapel Hill , North Carolina.
Hum Gene Ther. 2017 Jun;28(6):450-463. doi: 10.1089/hum.2017.038.
The infusion of healthy stem cells into a patient-termed "stem-cell therapy"-has shown great promise for the treatment of genetic and non-genetic diseases, including mucopolysaccharidosis type 1, Parkinson's disease, multiple sclerosis, numerous immunodeficiency disorders, and aplastic anemia. Stem cells for cell therapy can be collected from the patient (autologous) or collected from another "healthy" individual (allogeneic). The use of allogenic stem cells is accompanied with the potentially fatal risk that the transplanted donor T cells will reject the patient's cells-a process termed "graft-versus-host disease." Therefore, the use of autologous stem cells is preferred, at least from the immunological perspective. However, an obvious drawback is that inherently as "self," they contain the disease mutation. As such, autologous cells for use in cell therapies often require genetic "correction" (i.e., gene addition or editing) prior to cell infusion and therefore the requirement for some form of nucleic acid delivery, which sets the stage for the AAV controversy discussed herein. Despite being the most clinically applied gene delivery context to date, unlike other more concerning integrating and non-integrating vectors such as retroviruses and adenovirus, those based on adeno-associated virus (AAV) have not been employed in the clinic. Furthermore, published data regarding AAV vector transduction of stem cells are inconsistent in regards to vector transduction efficiency, while the pendulum swings far in the other direction with demonstrations of AAV vector-induced toxicity in undifferentiated cells. The variation present in the literature examining the transduction efficiency of AAV vectors in stem cells may be due to numerous factors, including inconsistencies in stem-cell collection, cell culture, vector preparation, and/or transduction conditions. This review summarizes the controversy surrounding AAV vector transduction of stem cells, hopefully setting the stage for future elucidation and eventual therapeutic applications.
将健康的干细胞注入患者体内（即“干细胞疗法”），在治疗遗传和非遗传疾病方面显示出巨大潜力，这些疾病包括1型黏多糖贮积症、帕金森病、多发性硬化症、多种免疫缺陷疾病以及再生障碍性贫血。用于细胞治疗的干细胞可以从患者自身采集（自体干细胞），也可以从另一个“健康”个体采集（异体干细胞）。使用异体干细胞伴随着潜在的致命风险，即移植的供体T细胞会排斥患者的细胞，这一过程称为“移植物抗宿主病”。因此，至少从免疫学角度来看，使用自体干细胞更为可取。然而，一个明显的缺点是，由于其本质上是“自身”细胞，它们含有疾病突变。因此，用于细胞治疗的自体细胞通常需要在细胞注入前进行基因“校正”（即基因添加或编辑），因此需要某种形式的核酸递送，这就引发了本文所讨论的腺相关病毒（AAV）争议。尽管AAV是迄今为止临床上应用最广泛的基因递送载体，但与其他更令人担忧的整合型和非整合型载体（如逆转录病毒和腺病毒）不同，基于AAV的载体尚未应用于临床。此外，关于AAV载体转导干细胞的已发表数据在载体转导效率方面并不一致，而在未分化细胞中，AAV载体诱导毒性的相关研究结果却大相径庭。文献中关于AAV载体在干细胞中转导效率的差异可能是由于多种因素造成的，包括干细胞采集、细胞培养、载体制备和/或转导条件的不一致。本综述总结了围绕AAV载体转导干细胞的争议，希望为未来的阐明及最终的治疗应用奠定基础。
