Ohyagi Masaki, Nagata Tetsuya, Ihara Kensuke, Yoshida-Tanaka Kie, Nishi Rieko, Miyata Haruka, Abe Aya, Mabuchi Yo, Akazawa Chihiro, Yokota Takanori
Department of Neurology and Neurological Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
Center for Brain Integration Research, Tokyo Medical and Dental University, Tokyo, Japan.
Nat Commun. 2021 Dec 22;12(1):7344. doi: 10.1038/s41467-021-26902-8.
Manipulating lymphocyte functions with gene silencing approaches is promising for treating autoimmunity, inflammation, and cancer. Although oligonucleotide therapy has been proven to be successful in treating several conditions, efficient in vivo delivery of oligonucleotide to lymphocyte populations remains a challenge. Here, we demonstrate that intravenous injection of a heteroduplex oligonucleotide (HDO), comprised of an antisense oligonucleotide (ASO) and its complementary RNA conjugated to α-tocopherol, silences lymphocyte endogenous gene expression with higher potency, efficacy, and longer retention time than ASOs. Importantly, reduction of Itga4 by HDO ameliorates symptoms in both adoptive transfer and active experimental autoimmune encephalomyelitis models. Our findings reveal the advantages of HDO with enhanced gene knockdown effect and different delivery mechanisms compared with ASO. Thus, regulation of lymphocyte functions by HDO is a potential therapeutic option for immune-mediated diseases.
利用基因沉默方法调控淋巴细胞功能在治疗自身免疫性疾病、炎症和癌症方面具有广阔前景。尽管寡核苷酸疗法已被证明在治疗多种疾病方面取得成功，但将寡核苷酸高效地体内递送至淋巴细胞群体仍然是一项挑战。在此，我们证明静脉注射由反义寡核苷酸（ASO）及其与α-生育酚缀合的互补RNA组成的异源双链寡核苷酸（HDO），与ASO相比，能以更高的效力、功效和更长的保留时间使淋巴细胞内源性基因表达沉默。重要的是，HDO介导的Itga4减少改善了过继转移和主动实验性自身免疫性脑脊髓炎模型中的症状。我们的研究结果揭示了与ASO相比，HDO具有增强的基因敲低效果和不同递送机制的优势。因此，通过HDO调节淋巴细胞功能是免疫介导疾病的一种潜在治疗选择。
