Engineered AAV Muscle-Targeting Compositions for Lower Liver Toxicity
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Conventional recombinant adeno-associated viruses (rAAVs) exhibit limited cell tropism, requiring high doses for effective delivery to tissues other than the liver, leading to liver toxicity and manufacturing challenges, and species-specific transduction efficiency varies, making preclinical mouse studies inaccurate for human applications.
Innovation Solution
Engineered AAV vectors with muscle-specific targeting moieties, such as RGD motifs, are developed to enhance cell and species-specific tropism, allowing efficient delivery of therapeutic cargo to muscle tissues.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional rAAVs with natural capsid variants are used for systemic delivery, then liver transduction is achieved, but transduction efficiency in other tissues (muscle, nervous system, cardiac muscle) is limited
Solution Approach 1:
The patent applies local quality by engineering specific regions of the AAV capsid protein with targeted amino acid substitutions. These localized modifications at specific capsid positions alter the virus's tissue tropism without changing the entire capsid structure, enabling selective enhancement of transduction efficiency for particular tissues such as muscle or liver while maintaining overall capsid functionality.
Solution Approach 2:
The patent employs parameter changes by systematically varying amino acid sequences at specific capsid positions to modulate tissue specificity. By changing the chemical properties, charge, or hydrophobicity of capsid residues through targeted substitutions, the invention adjusts the viral particle's interaction with tissue-specific receptors, thereby optimizing transduction for desired target tissues.
2Reliability
If large doses of conventional rAAV are administered to achieve transduction in non-liver tissues, then transduction efficiency improves, but liver toxicity increases
Solution Approach 1:
The patent applies local quality by engineering specific regions of the AAV capsid protein with targeted amino acid substitutions. These localized modifications at specific capsid positions alter the virus's tissue tropism without changing the entire capsid structure, enabling selective enhancement of transduction for particular tissues such as muscle or liver while maintaining overall capsid functionality.
Solution Approach 2:
The patent converts the harmful non-specific tropism of conventional AAVs into a benefit by engineering capsids with enhanced tissue-specific targeting. The natural tendency of AAV to accumulate in multiple tissues is redirected through targeted capsid modifications that favor specific tissue uptake, thereby reducing off-target liver toxicity while maintaining or improving transduction efficiency at the desired site.
3Quantity of substance
If conventional rAAV manufacturing is scaled up to dose adult patients, then sufficient viral quantity is produced, but manufacturing complexity and challenges increase
Solution Approach 1:
The patent employs parameter changes by systematically varying amino acid sequences at specific capsid positions to modulate tissue specificity. By changing the chemical properties, charge, or hydrophobicity of capsid residues through targeted substitutions, the invention adjusts the viral particle's interaction with tissue-specific receptors, thereby optimizing transduction for desired target tissues.
4Productivity
If preclinical studies are conducted in mouse models, then initial therapeutic assessment is achieved, but results do not accurately reflect primate and human responses due to species-specific transduction differences
Solution Approach 1:
The patent employs parameter changes by systematically varying amino acid sequences at specific capsid positions to modulate tissue specificity. By changing the chemical properties, charge, or hydrophobicity of capsid residues through targeted substitutions, the invention adjusts the viral particle's interaction with tissue-specific receptors, thereby optimizing transduction for desired target tissues.
Data Source
AI summary
Described herein are targeting moieties that can be capable of specifically targeting muscle cells and can include an n-mer motif. In some embodiments, the n-mer motif contains an RGD motif. Also described herein are vector systems, particles, polypeptides that can encode and/or contain one or more targeting moieties. Also described herein are methods of delivering a cargo to a cell, such as a muscle cell, using one or more of the targeting moieties described herein.