The atlas of RNase H antisense oligonucleotide distribution and activity in the CNS of rodents and non-human primates following central administration

被引：68

作者：

Jafar-nejad, Paymaan ^{[1
]}

Powers, Berit ^{[1
]}

Soriano, Armand ^{[1
]}

Zhao, Hien ^{[1
]}

Norris, Daniel A. ^{[1
]}

Matson, John ^{[1
]}

DeBrosse-Serra, Beatrice ^{[1
]}

Watson, Jamie ^{[1
]}

Narayanan, Padmakumar ^{[1
]}

Chun, Seung J. ^{[1
]}

Mazur, Curt ^{[1
]}

Kordasiewicz, Holly ^{[1
]}

Swayze, Eric E. ^{[1
]}

Rigo, Frank ^{[1
]}

机构：

[1] Ionis Pharmaceut Inc, Carlsbad, CA 92010 USA

来源：

NUCLEIC ACIDS RESEARCH | 2021年 / 49卷 / 02期

关键词：

D O I：

10.1093/nar/gkaa1235

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 nonneuronal 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.

引用

页码：657 / 673

页数：17

共 53 条

[1] A divalent siRNA chemical scaffold for potent and sustained modulation of gene expression throughout the central nervous system [J].