Systemic DNA/RNA heteroduplex oligonucleotide administration for regulating the gene expression of dorsal root ganglion and sciatic nerve.
Systemic DNA/RNA heteroduplex oligonucleotide administration for regulating the gene expression of dorsal root ganglion and sciatic nerve.
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DOI：
10.1016/j.omtn.2022.05.006
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发表时间：
2022-06-14
期刊：
影响因子：
--
通讯作者：
Yokota, Takanori
中科院分区：
文献类型：
--
作者：
Kaburagi, Hidetoshi;Nagata, Tetsuya;Enomoto, Mitsuhiro;Hirai, Takashi;Ohyagi, Masaki;Ihara, Kensuke;Yoshida-Tanaka, Kie;Ebihara, Satoe;Asada, Ken;Yokoyama, Hiroyuki;Okawa, Atsushi;Yokota, Takanori
神经性疼痛是一种异质性疾病，影响7%-10%的普通人群。迄今为止，有效和安全的治疗方法仍然有限。反义寡核苷酸（阿索）治疗打开了治疗脊髓性肌萎缩症的大门，许多正在进行的临床研究确定其治疗效用。用于神经性疼痛和周围神经疾病的阿索疗法需要在背根神经节（DRG）和坐骨神经（疼痛信号传导的关键组织）两者中的有效基因递送和敲低。我们以前开发了一种新的DNA/RNA异源双链寡核苷酸（HDO）技术，可以在肝脏中实现高效的基因敲除。在此，我们证明了静脉内注射HDO（包含ASO及其与α-生育酚缀合的互补RNA）使DRG和坐骨神经中的内源性基因表达沉默超过2倍，并且具有比单独的阿索更高的效力、功效和更广的分布。值得注意的是，我们通过原位杂交观察到所有大小的神经元DRG群体中的剧烈靶抑制。我们的研究结果确立了HDO递送作为神经性疼痛和周围神经疾病的研究和潜在治疗平台。Kaburagi及其同事证明，通过全身注射，DNA/RNA异源双链寡核苷酸（HDO）比亲本反义寡核苷酸更有效地分布于背根神经节和外周神经，具有显著的基因敲低效应。这项HDO技术预计将推动神经性疼痛和周围神经疾病的基因疗法的发展。
Neuropathic pain, a heterogeneous condition, affects 7%–10% of the general population. To date, efficacious and safe therapeutic approaches remain limited. Antisense oligonucleotide (ASO) therapy has opened the door to treat spinal muscular atrophy, with many ongoing clinical studies determining its therapeutic utility. ASO therapy for neuropathic pain and peripheral nerve disease requires efficient gene delivery and knockdown in both the dorsal root ganglion (DRG) and sciatic nerve, key tissues for pain signaling. We previously developed a new DNA/RNA heteroduplex oligonucleotide (HDO) technology that achieves highly efficient gene knockdown in the liver. Here, we demonstrated that intravenous injection of HDO, comprising an ASO and its complementary RNA conjugated to α-tocopherol, silences endogenous gene expression more than 2-fold in the DRG, and sciatic nerve with higher potency, efficacy, and broader distribution than ASO alone. Of note, we observed drastic target suppression in all sizes of neuronal DRG populations by in situ hybridization. Our findings establish HDO delivery as an investigative and potentially therapeutic platform for neuropathic pain and peripheral nerve disease. Kaburagi and colleagues demonstrated that a DNA/RNA heteroduplex oligonucleotide (HDO) distributed more efficiently to dorsal root ganglia and peripheral nerve with significant gene knockdown effect than the parent antisense oligonucleotides by systemic injection. This HDO technology is expected to lead to the development of gene-based therapies for neuropathic pain and peripheral nerve diseases.
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影响因子：
1.7
作者：
Fitzsimmons BL;Zattoni M;Svensson CI;Steinauer J;Hua XY;Yaksh TL
通讯作者：
Yaksh TL
影响因子：
16.2
作者：
Kordasiewicz HB;Stanek LM;Wancewicz EV;Mazur C;McAlonis MM;Pytel KA;Artates JW;Weiss A;Cheng SH;Shihabuddin LS;Hung G;Bennett CF;Cleveland DW
通讯作者：
Cleveland DW
影响因子：
5.3
作者：
Hains, BC;Saab, CY;Waxman, SG
通讯作者：
Waxman, SG
影响因子：
81.5
作者：
Colloca, Luana;Ludman, Taylor;Raja, Srinivasa N.
通讯作者：
Raja, Srinivasa N.
影响因子：
4.4
作者：
JACOBS, JM;MACFARLANE, RM;CAVANAGH, JB
通讯作者：
CAVANAGH, JB