title: A critical analysis of codon optimization in human therapeutics.
abstract: 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.
authors.affiliation: Department of Cell and Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA. Electronic address: vmauro@scripps.edu.
authors.forename: Vincent P
authors.initials: VP
authors.lastname: Mauro
authors.affiliation: Department of Cell and Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Chappell
mesh_terms: D000818:Animals; D003062:Codon; D005786:Gene Expression Regulation; D005818:Genetic Engineering / Q000379:methods; D015316:Genetic Therapy; D006801:Humans; D010455:Peptides / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use; D015202:Protein Engineering; D017393:RNA Editing; D012333:RNA, Messenger / Q000235:genetics; D012343:RNA, Transfer / Q000737:chemistry; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*
chemical_list: D003062:Codon; D010455:Peptides; D012333:RNA, Messenger; D011994:Recombinant Proteins; D012343:RNA, Transfer
keywords: A-to-I editing; codon optimization; gene therapy; mRNA therapy; tRNA wobble; vaccine