Cell-Penetrating Peptide Conjugates for Low-Toxicity Oligonucleotide Delivery
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Solution Overview
Problem
Current cell-penetrating peptides (CPPs) used for delivering antisense oligonucleotides in diseases like Duchenne muscular dystrophy (DMD) face challenges in efficacy and toxicity, limiting their therapeutic application in humans.
Innovation Solution
Development of peptides with a specific structure comprising two or more cationic domains and one hydrophobic domain, devoid of artificial amino acids, which enhance cell penetration and reduce toxicity when conjugated with therapeutic molecules.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current cell-penetrating peptides (CPPs) are used for delivering antisense oligonucleotides, then cell penetration is achieved, but toxicity increases and therapeutic efficacy is limited
Solution Approach 1:
The patent modifies the chemical structure of cell-penetrating peptides by replacing artificial amino acids (such as norleucine and norvaline) with natural amino acid equivalents (leucine and valine). This parameter change in molecular composition reduces immunogenicity and toxicity while preserving cell penetration capability, thereby improving therapeutic reliability for delivering antisense oligonucleotides in Duchenne muscular dystrophy treatment
Solution Approach 2:
The patent creates composite delivery systems by conjugating modified cell-penetrating peptides with antisense oligonucleotides. This composite structure combines the cell-penetrating properties of the peptide with the therapeutic function of the oligonucleotide, achieving effective delivery while reducing the toxicity associated with previous artificial peptide constructions
2Area of stationary object
If antisense oligonucleotides are administered systemically, then broad tissue distribution is achieved, but insufficient cell-penetrance and poor muscle tissue targeting occur
Solution Approach 1:
The patent employs modified cell-penetrating peptides as intermediary carriers that facilitate the delivery of antisense oligonucleotides across cell membranes. These peptide intermediaries enable systemic administration to achieve broad tissue distribution while ensuring adequate cell-penetrance through their enhanced membrane-transduction capability, which includes improved hydrophobicity and reduced charge that facilitates cellular uptake
Solution Approach 2:
The patent modifies physical-chemical parameters of the delivery system by adjusting the peptide's hydrophobicity and charge characteristics. These parameter changes enable the conjugate to penetrate cell membranes effectively while maintaining stability in physiological conditions, resolving the contradiction between broad distribution and sufficient cell-penetrance
Data Source
AI summary
The present invention relates to peptides, in particular cell-penetrating peptides, and to conjugates of such cell-penetrating peptides with a therapeutic molecule. The present invention further relates to use of such peptides or conjugates in methods of treatment or as a medicament, especially in the treatment of genetic disorders and in particular muscular dystrophies such as Duchenne muscular dystrophy.