Peptide-Nucleic Acid Conjugate for Myotonic Dystrophy Delivery
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current carrier peptides for delivering nucleic acid therapeutics, such as antisense oligonucleotides, face challenges in achieving effective cell penetration and distribution, particularly for trinucleotide repeat disorders like myotonic dystrophy, due to toxicity issues and limited efficacy, and have not been adequately tested for neuromuscular diseases with different pathologies.
Innovation Solution
Development of a conjugate with a peptide carrier having a total length of 40 amino acids or less, comprising two or more cationic domains and one or more hydrophobic domains, covalently linked to a nucleic acid with trinucleotide repeats, which enhances cell penetration and reduces toxicity, allowing effective delivery to non-degenerative muscle tissues.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional carrier peptides are used to deliver antisense oligonucleotides, then cell penetration is achieved, but toxicity increases and distribution characteristics deteriorate
Solution Approach 1:
The patent modifies the peptide carrier structure by changing parameters such as peptide length (40 amino acids or less), cationic domain composition (at least 4 arginine residues), and hydrophobic domain composition (at least 3 hydrophobic residues). These parameter changes optimize cell penetration while reducing toxicity compared to conventional longer peptides with higher cationic charge density.
Solution Approach 2:
The invention creates a composite structure combining a peptide carrier with specific cationic and hydrophobic domains conjugated to an antisense oligonucleotide. This composite design leverages the synergistic effects of cationic domains for cell membrane interaction and hydrophobic domains for membrane translocation, achieving effective delivery with reduced toxicity.
2Manufacturing precision
If antisense oligonucleotides are administered for trinucleotide repeat disorders, then splicing correction is achieved in vitro, but delivery to affected cells is insufficient
Solution Approach 1:
The peptide carrier acts as an intermediary vehicle that bridges the gap between antisense oligonucleotide therapy and target cells. The conjugated peptide enables the oligonucleotide to traverse cell membranes and reach intracellular targets, transforming in vitro splicing correction capability into in vivo therapeutic efficacy.
Solution Approach 2:
The patent optimizes delivery parameters by controlling peptide length (≤40 amino acids), cationic residue content (≥4 arginines), and hydrophobic residue content (≥3 hydrophobic residues). These parameter adjustments enhance cellular uptake and tissue distribution, enabling reliable in vivo delivery while maintaining splicing correction precision.
3Reliability
If peptide conjugates are designed for muscle delivery, then delivery to degenerative muscle is achieved, but efficacy in non-degenerative muscle tissues is insufficient
Solution Approach 1:
The peptide carrier is designed with universal delivery capabilities that function across different muscle tissue types. The combination of cationic domains for membrane interaction and hydrophobic domains for translocation creates a versatile delivery system effective in both degenerative and non-degenerative muscle tissues, expanding applicability beyond single-disease targets.
Data Source
AI summary
The present invention relates to conjugates formed from a cell-penetrating peptide carrier linked to a therapeutic molecule, wherein the peptide carrier is defined by specific domains and the therapeutic molecule is a nucleic acid formed of trinucleotide repeats. The present invention further relates to the use of such a conjugate in methods of treatment or as a medicament, especially in the treatment of trinucleotide repeat disorders such as myotonic dystrophy (DM1).