Codon optimization describes gene engineering approaches that use synonymous codon changes to increase protein production. Applications for codon optimization include recombinant protein drugs and nucleic acid therapies, including gene therapy, mRNA therapy, and DNA/RNA vaccines. However, recent reports indicate that codon optimization can affect protein conformation and function, increase immunogenicity, and reduce efficacy. We critically review this subject, identifying additional potential hazards including some unique to nucleic acid therapies. This analysis highlights the evolved complexity of codon usage and challenges the scientific bases for codon optimization. Consequently, codon optimization may not provide the optimal strategy for increasing protein production and may decrease the safety and efficacy of biotech therapeutics. We suggest that the use of this approach is reconsidered, particularly for in vivo applications.
Nucleotide sequence of the ribosomal protein gene cluster adjacent to the gene for RNA polymerase subunit beta in Escherichia coli
Gene F of bacteriophage phiX174. Correlation of nucleotide sequences from the DNA and amino acid sequences from the gene product
Defective presentation to class I-restricted cytotoxic T lymphocytes in vaccinia-infected cells is overcome by enhanced degradation of antigen
The codon Adaptation Index--a measure of directional synonymous codon usage bias, and its potential applications
Correlation between the abundance of Escherichia coli transfer RNAs and the occurrence of the respective codons in its protein genes: a proposal for a synonymous codon choice that is optimal for the E. coli translational system
Presentation of out-of-frame peptide/MHC class I complexes by a novel translation initiation mechanism
Codon optimization reveals critical factors for high level expression of two rare codon genes in Escherichia coli: RNA stability and secondary structure but not tRNA abundance
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Heterologous protein expression is enhanced by harmonizing the codon usage frequencies of the target gene with those of the expression host
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Quality over quantity: optimizing co-translational protein folding with non-'optimal' synonymous codons
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Functional Analysis of the Ser149/Thr149 Variants of Human Aspartylglucosaminidase and Optimization of the Coding Sequence for Protein Production
Selection of functional 2A sequences within foot-and-mouth disease virus; requirements for the NPGP motif with a distinct codon bias
LARP4 mRNA codon-tRNA match contributes to LARP4 activity for ribosomal protein mRNA poly(A) tail length protection
Codon Optimization in the Production of Recombinant Biotherapeutics: Potential Risks and Considerations
An evolutionary approach to optimizing glucose-6-phosphatase-α enzymatic activity for gene therapy of glycogen storage disease type Ia
Re-introducing non-optimal synonymous codons into codon-optimized constructs enhances soluble recovery of recombinant proteins from Escherichia coli
Genome-wide comparison of codon usage dynamics in mitochondrial genes across different species of amphibian genus Bombina
Identification and characterization of an IgG sequence variant with an 11 kDa heavy chain C-terminal extension using a combination of mass spectrometry and high-throughput sequencing analysis
Bioinformatic Identification of Rare Codon Clusters (RCCs) in HBV Genome and Evaluation of RCCs in Proteins Structure of Hepatitis B Virus
Codon usage clusters correlation: towards protein solubility prediction in heterologous expression systems in E. coli
Effects of codon optimization on coagulation factor IX translation and structure: Implications for protein and gene therapies
Robot Cookies - Plant Cell Packs as an Automated High-Throughput Screening Platform Based on Transient Expression
Codon optimized membrane cofactor protein expression in α 1, 3 galactosyltransferase knockout pig cells improve protection against cytotoxicity of monkey serum.
Effect of Mutations on mRNA and Globin Stability: The Cases of Hb Bernalda/Groene Hart and Hb Southern Italy.
Expression and serological application of recombinant epitope-repeat protein carrying an immunodominant epitope of Newcastle disease virus nucleoprotein
FVIII expression by its native promoter sustains long-term correction avoiding immune response in hemophilic mice
Composition, codon usage pattern, protein properties, and influencing factors in the genomes of members of the family Anelloviridae.
Cryptic prokaryotic promoters explain instability of recombinant neuronal sodium channels in bacteria.
BAX 335 hemophilia B gene therapy clinical trial results: potential impact of CpG sequences on gene expression.
Engineering rules that minimize germline silencing of transgenes in simple extrachromosomal arrays in C. elegans
Angiogenesis and nerve regeneration induced by local administration of plasmid pBud-coVEGF165-coFGF2 into the intact rat sciatic nerve.
Exploring the cancer-testis antigen BORIS to design a novel multi-epitope vaccine against breast cancer based on immunoinformatics approaches.
Synthetic human ABCB4 mRNA therapy rescues severe liver disease phenotype in a BALB/c.Abcb4-/- mouse model of PFIC3.
Effective, safe, and sustained correction of murine XLA using a UCOE-BTK promoter-based lentiviral vector.
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