Enhancing antisense efficacy with multimers and multi-targeting oligonucleotides (MTOs) using cleavable linkers.
Romesh R Subramanian1, Mark A Wysk1, Kathleen M Ogilvie2
1RaNA Therapeutics LLC, 790 Memorial Dr., Suite 203, Cambridge, MA 02139, USA.
Nucleic Acids Research
|October 9, 2015
Summary
Novel antisense oligonucleotide (ASO) multimers (MTOs) enhance in vivo potency and efficacy. These multi-targeting oligonucleotides offer improved biodistribution and therapeutic applications for single or multiple targets.
Area of Science:
- Oligonucleotide therapeutics
- Molecular biology
- Drug delivery systems
Background:
- Antisense oligonucleotides (ASOs) efficacy is enhanced by shorter lengths and high-affinity binders like locked nucleic acid (LNA) and 2',4'-constrained ethyl (cET).
- Current ASO designs face limitations in potency and targeted delivery.
Purpose of the Study:
- To develop a novel antisense oligonucleotide (ASO) design utilizing co-synthesized multimers (MTOs).
- To enhance in vivo potency, biodistribution, and therapeutic efficacy against single or multiple targets.
Main Methods:
- Development of novel ASO multimers (MTOs) using phosphodiester linkers for intracellular cleavage.
- Co-synthesis of ASO monomers as homo- or heterodimers/multimers.
- Evaluation of MTOs in both RNase H-activating and steric-blocking designs.
Main Results:
- MTOs demonstrate increased plasma protein binding and liver biodistribution compared to conventional ASOs.
- In vivo studies showed a ≈4-5-fold increase in potency and a ≈2-fold increase in efficacy.
- The novel MTO design effectively targets single or multiple genetic targets within a single construct.
Conclusions:
- Novel antisense oligonucleotide multimers (MTOs) represent a significant advancement in oligonucleotide therapeutics.
- MTOs offer enhanced in vivo performance, suggesting broad potential for treating various diseases.
- This innovative approach promises improved therapeutic outcomes through more effective gene silencing.
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