Short Antisense Compounds for ApoB Modulation
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Solution Overview
Problem
Current antisense compounds for reducing target RNA in vivo are limited by lack of specificity and efficacy at shorter lengths, leading to higher toxicity and costs, with previous studies indicating that compounds between 16 and 20 nucleobases are more effective.
Innovation Solution
Development of short antisense compounds 10 to 14 monomers in length with 2'-deoxyribonucleotide gap regions flanked by wings containing 1 to 3 high-affinity sugar-modified nucleotides, specifically targeted to ApoB for treating hypercholesterolemia and related conditions, utilizing phosphodiester and phosphorothioate linkages, and allowing for oral administration.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Object-generated harmful factors
If antisense compounds are shortened to reduce cost and toxicity, then treatment cost and toxicity are reduced, but target specificity and efficacy are compromised
Solution Approach 1:
The patent applies local quality by introducing high-affinity modified nucleotides (such as L-locked nucleic acid, BNA, or 2'-O-methoxyethyl modifications) at specific positions within the antisense compound sequence. These localized modifications enhance binding affinity and target specificity at critical regions while allowing the overall compound length to be reduced, thereby maintaining efficacy with shorter sequences that cost less and exhibit reduced toxicity.
Solution Approach 2:
The patent changes the chemical parameters of the nucleotides by incorporating chemically modified high-affinity nucleotides with altered sugar moieties (e.g., bridged nucleic acids, locked nucleic acids). These parameter changes in nucleotide structure increase binding strength and specificity, enabling shorter antisense compounds to achieve the same or better target reduction efficacy compared to longer unmodified compounds, thus reducing toxicity and treatment cost.
2Ease of manufacture
If antisense compound length is reduced to lower treatment cost, then cost of treatment is reduced, but potency and efficacy are diminished
Solution Approach 1:
The patent strategically places high-affinity modified nucleotides at specific positions (e.g., flanking a gap region or at key binding interfaces) within the antisense compound. This localized enhancement of binding affinity allows the compound to achieve high potency with fewer total nucleotides, reducing synthesis cost while maintaining or improving efficacy compared to longer unmodified compounds.
Solution Approach 2:
The patent creates composite antisense compounds by combining different types of nucleotides (modified high-affinity nucleotides with unmodified or differently modified nucleotides) in a single molecule. This composite structure leverages the high binding affinity of modified nucleotides at critical positions while using simpler nucleotides elsewhere, achieving high potency at lower cost by optimizing the composition rather than uniformly modifying the entire sequence.
3Power
If high-affinity modified nucleotides are incorporated to enhance potency, then potency and therapeutic index are improved, but compound complexity increases
Solution Approach 1:
The patent applies local quality by incorporating high-affinity modified nucleotides only at specific strategic positions within the antisense compound rather than uniformly throughout the entire sequence. This selective modification enhances potency at critical binding regions while keeping the rest of the compound simpler, thus improving therapeutic index without excessively increasing overall compound complexity.
Solution Approach 2:
The patent applies partial action by incorporating a limited number of high-affinity modified nucleotides (e.g., 1-3 modifications) into the antisense compound rather than modifying all nucleotides. This partial modification is sufficient to achieve the desired potency enhancement and therapeutic index improvement, avoiding the excessive complexity that would result from comprehensive modification of the entire sequence.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
These short antisense compounds demonstrate increased potency and reduced toxicity, achieving effective target RNA reduction at lower doses and potentially lower costs, with enhanced uptake in the gut and improved therapeutic index.
Implementation Method 1
an antisense compound hybridizes to a target nucleic acid and effects modulation of gene expression activity or function
Implementation Method 2
Chemically modified nucleosides are routinely used for incorporation into antisense compounds to enhance one or more properties, such as nuclease resistance
Data Source
AI summary
The present disclosure describes short antisense compounds, including such compounds comprising chemically-modified high-affinity monomers 8-16 monomers in length. Certain such short antisense compound are useful for the reduction of target nucleic acids and/or proteins in cells, tissues, and animals with increased potency and improved therapeutic index. Thus, provided herein are short antisense compounds comprising high-affinity nucleotide modifications useful for reducing a target RNA in vivo. Such short antisense compounds are effective at lower doses than previously described antisense compounds, allowing for a reduction in toxicity and cost of treatment. In addition, the described short antisense compounds have greater potential for oral dosing.