High-efficiency transduction of spinal cord motor neurons by intrauterine delivery of integration-deficient lentiviral vectors

JOURNAL OF CONTROLLED RELEASE

卷:273

Article

Ahmed, Sherif G.^1,2  Waddington, Simon N.^3,4  Boza-Moran, Maria Gabriela¹  Yanez-Munoz, Rafael J.¹ 

[1] Royal Holloway Univ London, Sch Biol Sci, Ctr Biomed Sci, AGCTlab Org, Egham TW20 0EX, Surrey, England

[2] Beni Suef Univ, Fac Pharm, Dept Pharmacol & Toxicol, Bani Suwayf, Egypt

[3] UCL, Inst Womens Hlth, London, England

[4] Univ Witwatersrand, Fac Hlth Sci, MRC Antiviral Gene Therapy Res Unit, Johannesburg, South Africa

关键词: Integration-deficient lentiviral vectors (IDLV);    Spinal cord;    In utero gene delivery;    Pseudotyping;   

DOI  :  10.1016/j.jconrel.2017.12.029

来源: Elsevier

【 摘 要 】

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 similar to 40% of spinal cord motor neurons, with other non-neuronal cells also transduced. Long-term expression studies revealed stable gene expression at 7 months 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.

【 授权许可】

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