CPP-Antisense Conjugates for DMD Exon 44 Intracellular Delivery
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Solution Overview
Problem
Existing antisense oligonucleotide therapeutics face limited intracellular delivery efficiency, hindering their effectiveness in treating Duchenne Muscular Dystrophy by restoring the reading frame of the DMD gene.
Innovation Solution
Development of compounds comprising a cell penetrating peptide (CPP) conjugated with an antisense compound (AC) that targets exon 44 of the DMD gene, enhancing intracellular delivery and altering splicing patterns to produce functional dystrophin proteins.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If antisense compounds are administered systemically, then they can reach the target tissue, but their intracellular delivery efficiency remains low
Solution Approach 1:
The patent employs cell-penetrating peptides (CPPs) as intermediary carriers to facilitate the intracellular delivery of antisense compounds. The CPPs conjugate with the antisense oligonucleotides and mediate their transport across the cell membrane, directly addressing the low intracellular delivery efficiency while maintaining therapeutic effectiveness.
Solution Approach 2:
The invention creates composite structures by chemically conjugating cell-penetrating peptides with antisense oligonucleotides. This composite material combines the cell-penetration capability of CPPs with the gene-targeting specificity of antisense compounds, simultaneously improving delivery efficiency and therapeutic reliability.
2Ease of operation
If carrier systems such as polymers or cationic liposomes are used, then intracellular delivery is facilitated, but delivery efficiency remains low
Solution Approach 1:
The patent changes the chemical and physical parameters of the delivery system by using small peptide-based carriers instead of large polymer or liposome carriers. This parameter change in carrier size and structure improves both the ease of intracellular entry and the actual delivery efficiency of the antisense compounds.
3Ease of operation
If cholesterol molecules are covalently attached, then intracellular delivery is enhanced, but delivery efficiency remains insufficient
Solution Approach 1:
The patent uses cell-penetrating peptides as intermediary carriers that directly mediate intracellular delivery of antisense compounds, replacing the cholesterol attachment approach. This intermediary system provides more efficient delivery while maintaining the enhancement of intracellular access.
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 CPP-AC conjugates significantly improve intracellular delivery and splicing correction, leading to enhanced production of functional dystrophin proteins, restoring muscle function in DMD models.
Implementation Method 1
a cell penetrating peptide (CPP) sequence
Implementation Method 2
hybridization of the AC with the target sequence alters the splicing pattern
Data Source
AI summary
Described herein in various embodiments are compositions comprising (a) a cyclic peptide; and (b) an antisense compound, wherein the antisense compound targets exon 44 of the DMD gene in a pre-mRNA sequence.