Mitochondrial Codon Editing for Controlled Translation Efficiency
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Solution Overview
Problem
Existing methods do not effectively address the influence of synonymous codons on translation efficiency and protein folding, particularly in mitochondrial translation, leading to impaired cellular energy production and cellular dysfunction.
Innovation Solution
Genetically modify mitochondrial genes to alter codon-anti-codon interactions, either increasing or decreasing translation efficiency by modifying the affinity of these interactions, thereby optimizing protein synthesis and cellular function.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If synonymous codons are used in mitochondrial genes, then translation efficiency varies, but this leads to impaired protein synthesis and cellular energy production
Solution Approach 1:
The patent applies parameter changes by modifying codon sequences in mitochondrial genes to optimize translation efficiency. Specifically, synonymous codons are selected and substituted to match the mitochondrial codon usage bias, thereby improving the affinity of codon-anticodon interactions and enhancing translation of mitochondrial mRNAs without altering the amino acid sequence of the encoded proteins.
2Productivity
If codon usage bias is not optimized, then translation efficiency varies, but this results in impaired protein folding and cellular dysfunction
Solution Approach 1:
The patent optimizes codon usage parameters to improve both translation efficiency and protein folding. By selecting synonymous codons that align with mitochondrial codon usage bias, the invention ensures more efficient translation elongation and proper protein folding, thereby preventing cellular dysfunction.
3Productivity
If mitochondrial translation is impaired, then protein synthesis is affected, but this leads to severe combined respiratory chain dysfunction and diminished ATP production
Solution Approach 1:
The patent addresses the contradiction by modifying codon sequences in mitochondrial genes to optimize translation efficiency. This ensures adequate synthesis of respiratory chain proteins, maintaining proper respiratory chain function and ATP production while preventing cellular energy deficit.
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
Enhances the proliferative capacity and altered phenotype of immune cells, such as T cells, by optimizing mitochondrial translation, which is beneficial for cell-based therapies like CAR-T cell therapies.
Implementation Method 1
modifying the affinity of a codon-anti-codon interaction during translation of the mRNA
Implementation Method 2
translation of a messenger RNA (mRNA) encoded by the mitochondrial gene
Data Source
AI summary
Provided are methods of genetically modifying cells. In certain embodiments, the methods comprise modifying a coding region of a mitochondrial gene of the cell. According to some embodiments, the modification results in increased translation of a messenger RNA (mRNA) encoded by the mitochondrial gene by increasing the affinity of a codon-anti-codon interaction during translation of the mRNA as compared to the affinity of the codon-anti-codon interaction prior to the modifying. In certain embodiments, the modification results in decreased translation of an mRNA encoded by the mitochondrial gene by decreasing the affinity of a codon-anti-codon interaction during translation of the mRNA as compared to the affinity of the codon-anti-codon interaction prior to the modifying. Also provided are populations of the genetically modified cells, compositions comprising such populations, and methods of administering the compositions to a subject as a cell-based therapy.