AGCTlab.org, Centre for Biomedical Sciences, School of Biological Sciences, Royal Holloway, University of London, Egham TW20 0EX, UK; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Beni-Suef University, Egypt.
The Institute for Women's Health, University College London, London, UK; MRC Antiviral Gene Therapy Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
J Control Release. 2018 Mar 10;273:99-107. doi: 10.1016/j.jconrel.2017.12.029. Epub 2017 Dec 28.
Integration-deficient lentiviral vectors (IDLVs) are promising gene delivery tools that retain the high transduction efficiency of standard lentiviral vectors, yet fail to integrate as proviruses and are instead converted into episomal circles. These episomes are metabolically stable and support long-term expression of transgenes in non-dividing cells, exhibiting a decreased risk of insertional mutagenesis. We have embarked on an extensive study to compare the transduction efficiency of IDLVs pseudotyped with different envelopes (vesicular stomatitis, Rabies, Mokola and Ross River viral envelopes) and self-complementary adeno-associated viral vectors, serotype-9 (scAAV-9) in spinal cord tissues after intraspinal injection of mouse embryos (E16). Our results indicate that IDLVs can transduce motor neurons (MNs) at extremely high efficiency regardless of the envelope pseudotype while scAAV9 mediates gene delivery to ~40% of spinal cord motor neurons, with other non-neuronal cells also transduced. Long-term expression studies revealed stable gene expression at 7months post-injection. Taken together, the results of this study indicate that IDLVs may be efficient tools for in utero cord transduction in therapeutic strategies such as for treatment of inherited early childhood neurodegenerative diseases.
整合缺陷型慢病毒载体（IDLVs）是一种很有前途的基因传递工具，它保留了标准慢病毒载体的高转导效率，但不能整合为前病毒，而是转化为附加体环。这些附加体在代谢上是稳定的，并支持非分裂细胞中转基因的长期表达，降低了插入突变的风险。我们进行了一项广泛的研究，比较了不同包膜（水疱性口炎、狂犬病、Mokola 和罗斯河病毒包膜）和自我互补的腺相关病毒载体，血清型-9（scAAV-9）包被的 IDLVs 在胚胎期（E16）小鼠脊柱内注射后脊髓组织中的转导效率。我们的结果表明，IDLVs 可以极高的效率转导运动神经元（MNs），而不管包膜假型如何，而 scAAV9 将基因传递给约 40%的脊髓运动神经元，其他非神经元细胞也被转导。长期表达研究显示，注射后 7 个月时基因表达稳定。总之，这项研究的结果表明，IDLVs 可能是治疗遗传性儿童期神经退行性疾病等治疗策略中胎儿脐带转导的有效工具。
