The atlas of RNase H antisense oligonucleotide distribution and activity in the CNS of rodents and non-human primates following central administration.
The atlas of RNase H antisense oligonucleotide distribution and activity in the CNS of rodents and non-human primates following central administration.
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中枢给药后RNaseH反义寡核苷酸在啮齿动物和非人灵长类动物中枢神经系统中的分布和活性图谱。
DOI：
10.1093/nar/gkaa1235
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发表时间：
2021-01-25
影响因子：
14.9
通讯作者：
Rigo F
中科院分区：
文献类型：
--
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
反义寡核苷酸(ASO)已成为一类新型药物，用于治疗包括神经系统适应症在内的多种疾病。Spinraza是一种调节SMN2RNA剪接的ASO，已经在脊髓肌萎缩症(SMA)患者中显示出深刻的疾病改善作用，为开发ASO治疗其他神经系统疾病提供了动力。虽然SMA专门影响脊髓运动神经元，但其他神经系统疾病影响到不同的中枢神经系统(CNS)区域、神经元和非神经元细胞。因此，重要的是确定ASO在所有主要中枢神经系统结构和细胞类型中的分布和活性，以便更好地了解哪些神经系统疾病适合ASO治疗。在这里，我们首次提出了ASO在小鼠、大鼠和非人类灵长类(NHP)中枢神经系统中的分布和活动的图谱，这些物种通常用于临床前治疗开发。在给啮齿动物中枢注射ASO后，我们观察到神经元、少突胶质细胞、星形胶质细胞和小胶质细胞中广泛分布的靶向RNA和靶RNA减少。NHP也是如此，尽管CNS体积更大，神经结构也更复杂。我们的结果表明，ASO药物非常适合于治疗广泛的神经疾病，而这些疾病没有有效的治疗方法。
Antisense oligonucleotides (ASOs) have emerged as a new class of drugs to treat a wide range of diseases, including neurological indications. Spinraza, an ASO that modulates splicing of SMN2 RNA, has shown profound disease modifying effects in Spinal Muscular Atrophy (SMA) patients, energizing efforts to develop ASOs for other neurological diseases. While SMA specifically affects spinal motor neurons, other neurological diseases affect different central nervous system (CNS) regions, neuronal and non-neuronal cells. Therefore, it is important to characterize ASO distribution and activity in all major CNS structures and cell types to have a better understanding of which neurological diseases are amenable to ASO therapy. Here we present for the first time the atlas of ASO distribution and activity in the CNS of mice, rats, and non-human primates (NHP), species commonly used in preclinical therapeutic development. Following central administration of an ASO to rodents, we observe widespread distribution and target RNA reduction throughout the CNS in neurons, oligodendrocytes, astrocytes and microglia. This is also the case in NHP, despite a larger CNS volume and more complex neuroarchitecture. Our results demonstrate that ASO drugs are well suited for treating a wide range of neurological diseases for which no effective treatments are available.
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影响因子：
64.8
作者：
Elitt MS;Barbar L;Shick HE;Powers BE;Maeno-Hikichi Y;Madhavan M;Allan KC;Nawash BS;Gevorgyan AS;Hung S;Nevin ZS;Olsen HE;Hitomi M;Schlatzer DM;Zhao HT;Swayze A;LePage DF;Jiang W;Conlon RA;Rigo F;Tesar PJ
通讯作者：
Tesar PJ
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：
11.2
作者：
McLoughlin HS;Moore LR;Chopra R;Komlo R;McKenzie M;Blumenstein KG;Zhao H;Kordasiewicz HB;Shakkottai VG;Paulson HL
通讯作者：
Paulson HL
影响因子：
3
作者：
Mazur, Curt;Fitzsimmons, Bethany;Wancewicz, Ed
通讯作者：
Wancewicz, Ed
影响因子：
2.9
作者：
Brichta L;Greengard P
通讯作者：
Greengard P