Antisense Oligonucleotide Conjugated with Cell-Penetrating Peptide for Muscle Targeting

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Solution Overview

Problem

Current drug delivery methods face challenges in effectively targeting and penetrating cell membranes, particularly for oligonucleotides, which hinders their therapeutic utility in treating muscle disorders like myotonic dystrophy and Duchenne muscular dystrophy due to insufficient cellular uptake.

Innovation Solution

The use of cell-penetrating peptides (CPPs) with specific sequences, such as (RXRR(B/X)R)2XB, conjugated to antisense oligonucleotides, enhances their uptake and functionality in muscle tissues by facilitating penetration across cell membranes, targeting specific muscle tissues including heart and skeletal muscles.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If oligonucleotides are used to treat muscle disorders, then therapeutic efficacy is improved, but cellular uptake is insufficient

Engineering Contradiction:

Improvetherapeutic efficacyVSAvoidinsufficient cellular uptake

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent applies composite materials by conjugating oligonucleotides with cell-penetrating peptides to create a hybrid molecule that combines the therapeutic properties of oligonucleotides with the cell-penetrating capabilities of peptides, thereby improving cellular uptake while maintaining therapeutic efficacy

Inventive Principle:

Principle #40Composite materials

Solution Approach 2:

The cell-penetrating peptide acts as an intermediary that facilitates the entry of oligonucleotides into muscle cells. The peptide sequence (RXRR(B/X)R)2XB serves as a mediator that enables the oligonucleotide to cross the cell membrane barrier, solving the insufficient cellular uptake problem

Inventive Principle:

Principle #24Intermediary (Mediator)

2Object-affected harmful factors

If cell-penetrating peptides are conjugated to oligonucleotides, then cellular uptake is improved, but device complexity increases

Engineering Contradiction:

Improvecellular uptakeVSAvoidcompound structure

Core Design Contradiction:

Object-affected harmful factorsVSDevice complexity

Solution Approach 1:

The patent applies parameter changes by modifying the chemical structure of the oligonucleotide through conjugation with cell-penetrating peptides. This changes the physical and chemical parameters of the compound, specifically adding cell-penetrating properties while maintaining the core oligonucleotide structure for therapeutic activity

Inventive Principle:

Principle #35Parameter changes

Data Source

PatentUS11236329B2Compound and method for treating myotonic dystrophy

Publication Date: 2022.02.01 SAREPTA THERAPEUTICS INC

AI summary

An antisense compound for use in treating myotonic dystrophy DM1 or DM2, a method of enhancing antisense targeting to heart and quadricep muscles, and a method for treating DM1 or DM2 in a mammalian subject are disclosed. The oligonucleotide has 8-30 bases, with at least 8 contiguous bases being complementary to the polyCUG or polyCCUG repeats in the 3′UTR region of dystrophia myotonica protein kinase (DMPK) mRNA in DM1 or DM2, respectively. Conjugated to the oligonucleotide is a cell-penetrating peptide having the sequence (RXRR(B/X)R)2XB, where R is arginine; B is β-alanine; and each X is —C(O)—(CH2)n—NH—, where n is 4-6. The antisense compound is effective to selectively block the sequestration of muscleblind-like 1 protein (MBNL1) and/or CUGBP, in heart and quadricep muscle in a myotonic dystrophy animal model.