Cleavable GalNAc Antisense Conjugates With Lower Kidney Exposure
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Solution Overview
Problem
Existing antisense compounds face challenges in efficiently delivering and maintaining activity within liver cells, particularly hepatocytes, due to issues with uptake and clearance, as well as potential immunogenicity and toxicity, limiting their therapeutic efficacy.
Innovation Solution
Conjugated antisense compounds are developed with a cleavable moiety attached via phosphodiester linkages, targeting the 5′ end, which enhance uptake into liver cells while minimizing interference with hybridization and splicing processes, and are designed to be cleaved efficiently, maintaining activity and reducing kidney exposure.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If antisense compounds are administered to target liver cells, then therapeutic efficacy is improved, but uptake efficiency and cellular delivery are insufficient
Solution Approach 1:
The patent employs cell-targeting moieties as intermediary components that mediate between the antisense compound and liver cells. These targeting moieties act as bridges that facilitate recognition and binding to specific cell surface receptors, thereby improving cellular uptake efficiency without compromising the therapeutic action of the antisense sequence
Solution Approach 2:
The invention creates composite antisense compounds by combining multiple functional components: the antisense oligonucleotide core, cell-targeting moieties for enhanced delivery, and cleavable linkers for controlled release. This composite structure integrates delivery enhancement with therapeutic function, resolving the contradiction between uptake efficiency and therapeutic efficacy
2Productivity
If conjugate groups are attached to enhance liver cell uptake, then delivery is improved, but interference with hybridization and splicing processes may occur
Solution Approach 1:
The patent segments the conjugate structure into distinct functional modules: a cell-targeting moiety connected via a cleavable linker to the antisense oligonucleotide. This segmentation allows the targeting component to perform its delivery function while the cleavable linker ensures separation before the antisense compound engages in hybridization, preventing interference with molecular recognition processes
Solution Approach 2:
The cell-targeting moiety performs preliminary action by facilitating cellular uptake and delivery of the antisense compound to the intracellular environment. The cleavable linker is designed to be cleaved under intracellular conditions, releasing the active antisense compound before it needs to perform hybridization, thus ensuring delivery enhancement without compromising subsequent molecular interactions
3Reliability
If conjugated antisense compounds are used to improve potency, then therapeutic effect is enhanced, but kidney exposure and potential toxicity increase
Solution Approach 1:
The patent applies local quality by incorporating cell-targeting moieties that provide selective affinity for liver cells. This localization strategy concentrates the therapeutic effect in the target organ (liver) while minimizing distribution to non-target organs (kidney), thereby enhancing potency at the target site while reducing off-target toxicity
Solution Approach 2:
The invention converts the potential harm of increased compound exposure into a benefit by using the cleavable linker design. The linker remains intact during circulation (protecting the compound) but is cleaved in the target cell (releasing active compound), transforming the exposure issue into a controlled delivery advantage that enhances potency while reducing systemic toxicity including kidney exposure
4Stability of the object's composition
If chemical modifications are incorporated to enhance nuclease resistance, then stability is improved, but pharmacokinetic properties and clearance rates are affected
Solution Approach 1:
The patent utilizes parameter changes by incorporating modified nucleosides that alter the physicochemical properties of the antisense oligonucleotide. These modifications change parameters such as charge distribution, hydrophobicity, and steric properties, which collectively enhance nuclease resistance while allowing optimization of pharmacokinetic properties including clearance rate through careful selection of modification types and positions
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
The conjugated antisense compounds demonstrate improved potency and delivery to hepatocytes, reduced kidney exposure, and maintained tolerability, offering enhanced therapeutic potential with fewer side effects.
Implementation Method 1
conjugated antisense compounds comprising an antisense oligonucleotide and a conjugate group, wherein the conjugate group comprises a cell-targeting moiety, a conjugate linker, and a cleavable moiety
Implementation Method 2
The principle behind antisense technology is that an antisense compound hybridizes to a target nucleic acid and modulates the amount, activity, and/or function of the target nucleic acid
Implementation Method 3
An example of modulation of RNA target function by degradation is RNase H-based degradation of the target RNA upon hybridization with a DNA-like antisense compound
Data Source
AI summary
Provided herein are oligomeric compounds with conjugate groups. In certain embodiments, the oligomeric compounds are conjugated to N-Acetylgalactosamine.