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The atlas of RNase H antisense oligonucleotide distribution and activity in the CNS of rodents and non-human primates following central administration.
- Source :
-
Nucleic acids research [Nucleic Acids Res] 2021 Jan 25; Vol. 49 (2), pp. 657-673. - Publication Year :
- 2021
-
Abstract
- 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.<br /> (© The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research.)
- Subjects :
- Animals
Central Nervous System cytology
Female
In Situ Hybridization
Injections, Intraventricular
Injections, Spinal
Macaca fascicularis
Male
Neuroglia chemistry
Neurons chemistry
Oligonucleotides, Antisense administration & dosage
Organ Specificity
RNA, Long Noncoding analysis
RNA, Long Noncoding antagonists & inhibitors
RNA, Long Noncoding genetics
Rats, Sprague-Dawley
Ribonuclease H
Tissue Distribution
Central Nervous System chemistry
Mice metabolism
Oligonucleotides, Antisense pharmacokinetics
Primates metabolism
Rats metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1362-4962
- Volume :
- 49
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Nucleic acids research
- Publication Type :
- Academic Journal
- Accession number :
- 33367834
- Full Text :
- https://doi.org/10.1093/nar/gkaa1235