Cyclic Cell-Penetrating Peptide Conjugates for Antisense Delivery
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Solution Overview
Problem
Existing therapeutic antisense compounds face limited intracellular delivery efficiency, hindering their effectiveness in treating diseases caused by aberrant gene transcription, splicing, and translation.
Innovation Solution
Compositions comprising cyclic cell-penetrating peptides (cCPP) conjugated with antisense compounds (AC) through linkers, utilizing modified nucleotides and nucleic acids for enhanced intracellular delivery and splicing modulation, including siRNA, miRNA, ribozymes, and CRISPR machinery.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If carrier systems such as polymers or cationic liposomes are used to facilitate intracellular delivery of antisense compounds, then delivery capability is improved, but delivery efficiency remains low and system complexity increases
Solution Approach 1:
The patent uses composite materials by combining antisense compounds with cell-penetrating peptides (CPPs) and linkers to create a conjugate system. This composite approach enables intracellular delivery without requiring complex external carrier systems like polymers or liposomes, thereby improving delivery capability while reducing system complexity
Solution Approach 2:
The cell-penetrating peptide component of the conjugate provides self-service by inherently possessing cell membrane penetration capability. The CPP-mediated internalization mechanism allows the antisense compound to deliver itself into cells without requiring external carrier assistance, simplifying the overall delivery system
2Reliability
If chemical modification of the antisense construct is performed to facilitate delivery, then intracellular access is improved, but manufacturing complexity and cost increase
Solution Approach 1:
The delivery system is segmented into distinct functional modules: the antisense compound moiety, the cell-penetrating peptide moiety, and a linker connecting them. This segmentation allows each component to be optimized and synthesized separately using established chemical methods, then assembled through well-defined conjugation chemistry, thereby maintaining manufacturing simplicity while achieving improved intracellular access
Solution Approach 2:
The linker serves as an intermediary component that connects the antisense compound to the cell-penetrating peptide. This intermediary structure enables controlled conjugation between the two moieties through specific chemical reactions, facilitating delivery improvement while maintaining ease of manufacture through modular assembly
3Adaptability or versatility
If conventional antisense compounds are administered systemically, then broad therapeutic application is achieved, but intracellular delivery efficiency is limited
Solution Approach 1:
The cell-penetrating peptide component provides universal cell entry capability that works across different cell types and tissue barriers. This multi-functional design allows the antisense conjugate to maintain broad therapeutic applicability while overcoming the intracellular delivery efficiency limitation through the CPP-mediated entry mechanism
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 compositions achieve improved intracellular delivery and splicing modulation, resulting in the expression of functional or more functional re-spliced proteins, effectively treating genetic diseases such as Duchenne muscular dystrophy and other disorders by enhancing the potency of antisense compounds.
Implementation Method 1
cyclic cell penetrating peptide (cCPP) sequence
Implementation Method 2
hybridization of the AC with the target sequence reduces or prevents splicing
Data Source
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AI summary
Provided herein are compounds comprising cyclic cell penetrating peptides and antisense compounds. Also provided herein are methods of modulating splicing, inhibiting or regulating translation, mediating degradation, blocking expansions of nucleotide repeats, and treating disease using the aforementioned compounds.