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US 2023/0146324 A1Published application
Multiparametric nucleic acid optimization
AssigneeModernaTX, Inc.
InventorsJohn van Wicheren REYNDERS, III, Tirtha CHAKRABORTY, Stephen HOGE, Iain James MCFADYEN
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Abstract
The present disclosure provides multiparametric codon optimization methods to improve at least a property in a candidate nucleic acid sequence, for example the translation efficacy of a therapeutic mRNA.
Claims19
A multiparametric method for optimizing a candidate nucleic acid sequence, the method comprising at least one optimization method selected from:
- (i) modifying at least one subsequence in the candidate nucleic acid sequence to generate a ramp subsequence;
- (ii) substituting at least one codon in the candidate nucleic acid sequence with an alternative codon to increase or decrease uridine content to generate a uridine-modified sequence;
- (iii) substituting at least one codon in the candidate nucleic acid sequence or the uridine-modified sequence with a faster recharging codon;
- (iv) substituting at least one codon in the candidate nucleic acid sequence with an alternative codon having a higher codon frequency in the synonymous codon set;
- (v) substituting at least one natural nucleobase in the candidate nucleic acid sequence with an alternative synthetic nucleobase;
- (vi) substituting at least one internucleoside linkage in the candidate nucleic acid sequence with a non-natural internucleoside linkage;
- and,
- (vii) combinations thereof. wherein the resulting optimized nucleic acid sequence has at least one optimized property with respect to the candidate nucleic acid sequence.
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