Delivering RNA-Targeted
Therapeutics
Delivering RNA-Targeted
Therapeutics
Preliminary research has demonstrated that investigational RNA-targeted therapeutics can penetrate tissues throughout the central nervous system (CNS) and are active across a wide range of cell types in the CNS.1-6
These findings offer the opportunity to develop RNA-targeted therapeutics for many types of neurologic diseases.1
Investigational RNA-targeted therapeutics can be delivered to the spinal cord and deep regions within the brain, including the hippocampus, pons, and amygdala.1-4
Dose Response and Accumulation of
Investigational RTTs in Mouse CNS Tissue1,a,b
aEach of the symbols (ie, circle, square, diamond, triangle) represents data from a single mouse at the dose plotted. bRTT used in the study targets Malat1 RNA.
CNS, central nervous system; PBS, phosphate-buffered saline; RTID, RNA-targeted investigational drug; RTT, RNA-targeted therapeutic.
Broad distribution of investigational RTTs and their activity in different brain structures and the spinal cord potentially offers the opportunity to develop these therapeutics for many types of neurological diseases that originate in the spinal cord and deep within the CNS.
Research in animal models has shown investigational RNA-targeted therapeutics are active in neurons, microglia, astrocytes, and oligodendrocytes.1-4
Dose-Dependent Reduction of mRNA With Investigational RTTs in All Four Major CNS Cell Types in Rodents1,a
aRTT used in the study targets Malat1 RNA.
CNS, central nervous system; ED50, effective dose; mRNA, messenger RNA; PBS, phosphate-buffered saline; RTT, RNA-targeted therapeutic.
Investigational RTTs can target the major cell types throughout the CNS, including neurons, oligodendrocytes, astrocytes, and microglia.
In human patients, investigational RNA-targeted therapeutics have been shown to distribute within the CNS.7
To see how this technology functions in the CNS, please watch the video below:
Learn more about Ionis’ approach to screening investigational RNA-targeted therapeutics and its pipeline candidates.
References
- Jafar-Nejad P, Powers B, Soriano A, et al. The atlas of RNase H antisense oligonucleotide distribution and activity in the CNS of rodents and non-human primates following central administration. Nucleic Acids Res. 2021;49(2):657-673.
- Korobeynikov VA, Lyashchenko AK, Blanco-Redondo B, Jafar-Nejad P, Shneider NA. Antisense oligonucleotide silencing of FUS expression as a therapeutic approach in amyotrophic lateral sclerosis. Nat Med. 2022;28(1):104-116.
- Mazur C, Powers B, Zasadny K, et al. Brain pharmacology of intrathecal antisense oligonucleotides revealed through multimodal imaging. JCI Insight. 2019;4(20):e129240.
- Mortberg MA, Gentile JE, Nadaf NM, et al. A single-cell map of antisense oligonucleotide activity in the brain. Nucleic Acids Res. 2023;51(14):7109-7124.
- Edwards AL, Collins JA, Junge C, et al. Exploratory tau biomarker results from a multiple ascending-dose study of BIIB080 in Alzheimer disease: a randomized clinical trial. JAMA Neurol. 2023;80(12):1344-1352.
- Finkel RS, Chiriboga CA, Vajsar J, et al. Treatment of infantile-onset spinal muscular atrophy with nusinersen: a phase 2, open-label, dose-escalation study. Lancet. 2016;388(10063):3017-3026.
- Bennett CF, Krainer AR, Cleveland DW. Antisense oligonucleotide therapies for neurodegenerative diseases. Annu Rev Neurosci. 2019;42:385-406.
