Comparative route of administration studies using therapeutic siRNAs show widespread gene modulation in Dorset sheep.
Comparative route of administration studies using therapeutic siRNAs show widespread gene modulation in Dorset sheep.
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DOI：
10.1172/jci.insight.152203
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发表时间：
2021-12-22
期刊：
影响因子：
8
通讯作者：
Khvorova A
中科院分区：
文献类型：
--
作者：
Ferguson CM;Godinho BM;Alterman JF;Coles AH;Hassler M;Echeverria D;Gilbert JW;Knox EG;Caiazzi J;Haraszti RA;King RM;Taghian T;Puri A;Moser RP;Gounis MJ;Aronin N;Gray-Edwards H;Khvorova A
siRNA包含一类可以编程以沉默任何靶基因的药物。化学工程努力导致二价siRNA（di-siRNA）的开发，其支持在直接脑脊液（CSF）施用后在啮齿动物和非人灵长类动物脑中的稳健和长期功效。寡核苷酸在CNS中的分布是不均匀的，限制了临床应用。CSF输注位置和给药方案对相对蓄积的影响，特别是在大型动物中，尚未得到充分表征。据我们所知，我们报告了第一个系统的比较研究，调查了3种给药途径的影响-纹状体内（i.s.），静脉注射，和鞘内导管至小脑延髓池（ITC）-和2种给药方案-单次和通过植入的储库装置重复-对多赛特绵羊CNS中di-siRNA分布和积累的影响。CSF注射（i. c. v.和ITC）导致在脑区的分布和蓄积相似。重复给药增加了均匀性，脑深部蓄积相对较大。相反，i.s.行政部门支持针对具体区域的交付。这些结果表明，给药方案，而不是CSF输注放置，可以均衡siRNA在整个大脑中的积累和功效。这些发现为在CNS中使用siRNA疗法的临床前和临床研究的规划和执行提供了信息。
siRNAs comprise a class of drugs that can be programmed to silence any target gene. Chemical engineering efforts resulted in development of divalent siRNAs (di-siRNAs), which support robust and long-term efficacy in rodent and nonhuman primate brains upon direct cerebrospinal fluid (CSF) administration. Oligonucleotide distribution in the CNS is nonuniform, limiting clinical applications. The contribution of CSF infusion placement and dosing regimen on relative accumulation, specifically in the context of large animals, is not well characterized. To our knowledge, we report the first systemic, comparative study investigating the effects of 3 routes of administration — intrastriatal (i.s.), i.c.v., and intrathecal catheter to the cisterna magna (ITC) — and 2 dosing regimens — single and repetitive via an implanted reservoir device — on di-siRNA distribution and accumulation in the CNS of Dorset sheep. CSF injections (i.c.v. and ITC) resulted in similar distribution and accumulation across brain regions. Repeated dosing increased homogeneity, with greater relative deep brain accumulation. Conversely, i.s. administration supported region-specific delivery. These results suggest that dosing regimen, not CSF infusion placement, may equalize siRNA accumulation and efficacy throughout the brain. These findings inform the planning and execution of preclinical and clinical studies using siRNA therapeutics in the CNS.
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影响因子：
14.9
作者：
Jafar-Nejad P;Powers B;Soriano A;Zhao H;Norris DA;Matson J;DeBrosse-Serra B;Watson J;Narayanan P;Chun SJ;Mazur C;Kordasiewicz H;Swayze EE;Rigo F
通讯作者：
Rigo F
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
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影响因子：
4.6
作者：
Kounda, Sunil;Elkin, Rena;Tannenbaum, Allen
通讯作者：
Tannenbaum, Allen
影响因子：
14.9
作者：
Hassler MR;Turanov AA;Alterman JF;Haraszti RA;Coles AH;Osborn MF;Echeverria D;Nikan M;Salomon WE;Roux L;Godinho BMDC;Davis SM;Morrissey DV;Zamore PD;Karumanchi SA;Moore MJ;Aronin N;Khvorova A
通讯作者：
Khvorova A
影响因子：
17.1
作者：
Iliff JJ;Wang M;Liao Y;Plogg BA;Peng W;Gundersen GA;Benveniste H;Vates GE;Deane R;Goldman SA;Nagelhus EA;Nedergaard M
通讯作者：
Nedergaard M