Exon Skipping Oligonucleotide Conjugates for Muscular Dystrophy
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Solution Overview
Problem
Current treatments for Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are inadequate due to aberrant mRNA splicing events that disrupt dystrophin production, leading to defective or non-functional dystrophin proteins.
Innovation Solution
A pharmaceutical composition comprising an antisense oligonucleotide conjugate with a cell penetrating peptide covalently attached to a nucleic acid analog, along with surfactants, sugars, and buffering agents, specifically designed to induce exon skipping in the human dystrophin gene, allowing for the production of functional dystrophin protein by hybridizing with pre-processed mRNA and promoting differential splicing.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional treatments are used for DMD/BMD, then current standard therapy is provided, but therapeutic efficacy is inadequate due to aberrant mRNA splicing
Solution Approach 1:
The patent uses antisense oligonucleotide conjugates as intermediary molecules that bind to pre-mRNA to redirect splicing. These conjugates consist of a nucleic acid analog (antisense oligonucleotide) covalently attached to a cell-penetrating peptide, acting as a mediator between the genetic material and the cellular machinery to correct aberrant splicing events and restore functional dystrophin production
Solution Approach 2:
The patent modifies the chemical parameters of oligonucleotide therapy by creating conjugates with cell-penetrating peptides and optimizing formulation parameters (surfactants, sugars, buffering agents). This changes the physical-chemical properties to enable cellular uptake and improve therapeutic efficacy, transforming the oligonucleotide from a non-functional form to an active therapeutic agent
2Reliability
If antisense oligonucleotide conjugates are administered, then exon skipping is induced to produce functional dystrophin, but delivery efficiency is challenged due to cellular uptake barriers
Solution Approach 1:
The patent creates composite therapeutic agents by covalently linking antisense oligonucleotides (nucleic acid component) with cell-penetrating peptides (protein component). This composite structure combines the splicing-modulating capability of oligonucleotides with the cell-penetrating ability of peptides, enabling efficient cellular delivery and functional dystrophin production
Solution Approach 2:
The cell-penetrating peptide acts as an intermediary that facilitates cellular uptake of the oligonucleotide conjugate. The peptide component mediates transport across the cell membrane, enabling the oligonucleotide to reach its intracellular target and induce exon skipping
3Manufacturing precision
If oligonucleotide conjugates are used to target specific exons, then precise splicing control is achieved, but formulation stability is compromised
Solution Approach 1:
The patent optimizes formulation parameters including pH (buffering agents), ionic strength, and composition (surfactants, sugars) to stabilize the oligonucleotide conjugate. By adjusting these physical-chemical parameters, the formulation maintains stability while preserving the conjugate's ability to target specific exons with precision
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 composition effectively increases the levels of functional dystrophin protein in muscle cells, providing therapeutic benefits for DMD and BMD by restoring a functional dystrophin transcript and improving muscle function.
Implementation Method 1
hybridizing with pre-processed mRNA and promoting differential splicing
Data Source
AI summary
Composition comprising: (a) an antisense oligonucleotide conjugate comprising a cell penetrating peptide covalently attached to a nucleic acid analog, or a pharmaceutically acceptable salt thereof, wherein the cell penetrating peptide includes at least two positively charged amino acids; (b) one or more surfactants; (c) one or more sugars; and (d) one or more buffering agents are provided herein.