DMD Exon Splicing Enhancer and sgRNA for Durable Gene Correction
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Solution Overview
Problem
Current treatments for Duchenne muscular dystrophy (DMD) are limited to symptom relief and do not effectively address the underlying genetic mutations, leading to progressive muscle and heart dysfunction, with existing drugs having low efficiency, high cost, and limited applicability to specific mutations.
Innovation Solution
Development of a Duchenne muscular dystrophy-related exon splicing enhancer and gene editing tool using CRISPR nuclease, antisense oligonucleotides, and adeno-associated virus (AAV) vectors to induce exon skipping and modify pathogenic mutations, restoring Dystrophin protein expression.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current drugs are used to treat DMD, then symptom relief is achieved, but treatment efficacy is low and continuous administration is required
Solution Approach 1:
The patent uses gene editing tools (CRISPR-Cas9, base editors, prime editors) to make permanent genetic corrections before disease progression occurs, or to restore dystrophin expression early in the disease course. This preliminary genetic intervention eliminates the need for continuous drug administration by addressing the root cause at the DNA level, providing durable therapeutic effects that persist throughout the patient's lifetime.
Solution Approach 2:
The patent replaces the mechanical/systemic approach of continuous drug administration with a biological/gene-level intervention. Instead of using small molecules or biologics that require repeated dosing, the invention employs gene editing machinery to permanently modify the DMD gene, substituting a one-time genetic correction for lifelong pharmacological treatment.
2Reliability
If current drugs are used to treat DMD, then some symptom relief is provided, but the treatment cost is extremely high
Solution Approach 1:
The patent enables the patient's own cells to produce functional dystrophin protein through gene editing. By correcting the genetic defect in situ, the body's cellular machinery is harnessed to self-produce the needed therapeutic protein, eliminating the need for expensive external drug supply and reducing long-term treatment costs.
Solution Approach 2:
The patent performs gene editing as a one-time preliminary intervention that establishes permanent therapeutic effect. This upfront genetic correction avoids the cumulative cost of lifelong expensive drug administration, making the treatment economically sustainable despite the initial investment in gene editing procedures.
3Adaptability or versatility
If current drugs are used to treat DMD, then treatment is available, but they only target specific mutations leaving gaps for patients with different genetic mutations
Solution Approach 1:
The patent employs gene editing tools that can be programmed to target different mutations through customizable guide RNAs and editing sequences. The same core gene editing platform (CRISPR-Cas9, base editors, prime editors) can be adapted to correct various types of DMD mutations including deletions, duplications, and point mutations, providing a universal therapeutic approach that covers all mutation types rather than requiring separate drugs for each mutation.
Solution Approach 2:
The patent changes the therapeutic parameter from mutation-specific small molecule binding to programmable DNA sequence recognition. By using guide RNAs with variable sequences that can be designed to match any target mutation, the system achieves broad mutation coverage while maintaining high specificity, allowing the same therapeutic platform to address diverse genetic defects through parameter customization.
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 gene editing tool effectively modifies pathogenic mutations in DMD mouse models and human cells, restoring Dystrophin protein function, improving muscle and heart function, and prolonging survival.
Implementation Method 1
utilizing CRISPR nuclease and antisense oligonucleotides to induce exon skipping in the DMD gene
Implementation Method 2
a fusion protein of cytosine deaminase and Cas9 mutant delivered via adeno-associated viral vectors to modify pathogenic mutations in the DMD gene
Implementation Method 3
a fusion protein of cytosine deaminase and Cas9 mutant
Data Source
AI summary
A duchenne muscular dystrophy-related exonic splicing enhancer, sgRNA and gene editing tool can be applied in the preparation of drugs for treating duchenne muscular dystrophy. The gene editing tool designed on the basis of cytosine deaminase AID mutants and Cas9 mutants can perform site-specific modification on a mammalian genome by using an adeno-associated virus (AAV) as a vector. By optimizing an encoding nucleic acid sequence and an element composition structure of the editing tool, site-specific targeted modification of mammalian genetic material DNA can be efficiently achieved; and by performing targeted genetic manipulation on the nucleic acid sequence carrying disease mutations, a pathogenic mutation cannot be retained in a mature protein amino acid sequence or the pathogenic mutation cannot perform its function, so that the purpose of treating various gene mutation type genetic rare diseases is achieved, and the advantages of high efficiency, safety and stability are achieved.