Antisense Compound Delivery via Cell-Penetrating Peptides
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Solution Overview
Problem
Existing antisense compounds face challenges in efficiently delivering therapeutic moieties to intracellular compartments and achieving specific tissue distribution, leading to limited efficacy in modulating mRNA splicing for therapeutic purposes.
Innovation Solution
The development of compositions that include a therapeutic moiety (TM) and a cell-penetrating peptide (CPP), where the TM is an antisense compound (AC) that binds to splice elements or cis-acting splice regulatory elements of target transcripts, modulating splicing and enhancing intracellular delivery through CPPs.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If antisense compounds are administered systemically, then tissue distribution can be achieved, but intracellular delivery efficiency remains low
Solution Approach 1:
The patent employs cell-penetrating peptides (CPPs) as intermediary carriers that facilitate the intracellular delivery of antisense compounds. The CPPs bind to the antisense compounds and mediate their transport across the cell membrane, thereby resolving the contradiction between achieving tissue distribution and maintaining low intracellular delivery efficiency
Solution Approach 2:
The invention creates composite structures by conjugating antisense compounds with cell-penetrating peptides. This composite material combines the gene-modulating capability of antisense compounds with the cell-penetration ability of CPPs, simultaneously achieving both tissue distribution and efficient intracellular delivery
2Productivity
If carrier systems such as polymers or cationic liposomes are used to facilitate intracellular delivery, then delivery efficiency improves, but tissue distribution becomes narrow
Solution Approach 1:
The patent uses relatively small, transient cell-penetrating peptides instead of large, complex carrier systems like polymers or liposomes. These peptides provide sufficient delivery efficiency while being less restrictive of tissue distribution, effectively replacing bulky carrier systems with more versatile smaller molecules
Solution Approach 2:
The invention changes the physical and chemical parameters of the delivery system by using peptides with specific properties (small size, positive charge, amphipathic structure) rather than large polymeric or liposomal carriers. This parameter change enables both efficient intracellular delivery and broader tissue distribution
3Productivity
If existing delivery technologies are used, then intracellular delivery can be achieved, but off-target interactions increase
Solution Approach 1:
The patent designs cell-penetrating peptides with specific local properties (amphipathic structure, specific amino acid sequences) that enable selective interaction with target cells. This localized optimization of peptide properties enhances delivery efficiency while minimizing off-target interactions through improved specificity
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
This approach effectively modulates splicing by inducing exon skipping, leading to frameshifts and nonsense-mediated decay, thereby reducing the expression of target proteins and treating genetic diseases associated with aberrant gene transcription, splicing, and translation.
Implementation Method 1
The CPP may enhance intracellular deliver of the AC to enhance the effectiveness of the AC to modulate splicing of the target transcript
Implementation Method 2
the AC binds to at least a portion of a splice element (SE) or cis-acting splice regulatory element (SRE) of the target transcript, or in proximity to a splice element or a cis-acting splice regulatory element of the target transcript, to modulate splicing of the target transcript
Implementation Method 3
Splicing refers to a process in which introns (intervening sequences) are removed from the pre-mRNA and exons (coding sequences) are ligated together to form a mature mRNA
Data Source
AI summary
Compounds include at least one cyclic cell penetrating peptide (cCPP) conjugated to an antisense compound (AC). The AC modulates splicing of an RNA transcript. For example, the AC induces exon skipping. Exon skipping can result in down-regulation of expression or activity of a protein. Exon skipping may cause a frameshift in a resulting mRNA. The frameshift may result in a premature termination codon. The frameshift may result in nonsense mediated decay.