Oregon Health & Science University, Pape Family Pediatric Research Institute, L321, Portland, United States.
Curr Gene Ther. 2017;16(5):329-337. doi: 10.2174/1566523217666170113165407.
Fanconi anemia (FA) is an autosomal recessive, multisystem DNA repair disorder with prominent defects in the hematopoietic stem cell maintenance that result in the progressive attrition and failure in the early school age. Allogeneic stem cell transplantation has proved curative for patients with suitable donors. This, along with the characteristic survival advantage of phenotypically normal over non-corrected FA stem cells underscores the compelling rationale for stem cell gene therapy in the FA. While integrating lentiviral vectors (LV) have become the preferred platform for genetic correction in several hematologic and immunodeficiency disorders, the residual oncogenic potential by these vectors raises concerns in the FA stem cells about insertional mutagenic genetic lesions. On this backdrop, investigators are developing a new generation of non-integrating viral vectors capable of nuclear persistence through serial mitotic cycles and stable under selection to offset the comparatively lower transduction rates. Here, we review the competing approaches to develop such non-integrating lentiviral (NILV) episome vectors that faithfully replicate in the stem cells.
范可尼贫血症（FA）是一种常染色体隐性、多系统 DNA 修复障碍，造血干细胞维持中存在明显缺陷，导致造血干细胞在早期学龄期逐渐耗竭和衰竭。对于有合适供体的患者，同种异体干细胞移植已被证明是一种有效的治疗方法。这一点，以及表型正常的 FA 干细胞比未经校正的 FA 干细胞具有明显的生存优势，突出了 FA 干细胞基因治疗的强烈合理性。虽然整合慢病毒载体（LV）已成为几种血液和免疫缺陷疾病遗传矫正的首选平台，但这些载体的残留致癌潜能在 FA 干细胞中引起了对插入突变遗传损伤的担忧。在此背景下，研究人员正在开发新一代非整合病毒载体，这些载体能够通过连续的有丝分裂周期在核内持续存在，并通过选择稳定下来，以抵消相对较低的转导率。在这里，我们回顾了开发这种非整合慢病毒（NILV）附加体载体的竞争方法，这些载体能够在干细胞中进行忠实的复制。
