Transgene codon usage drives viral fitness and therapeutic efficacy in oncolytic adenoviruses

Area of Science:

• Oncolytic virotherapy
• Molecular biology
• Gene therapy

Background:

• Oncolytic adenoviruses are engineered to target and destroy cancer cells.
• Attenuated viral replication and loss of oncolytic effects hinder clinical translation.
• Altering codon usage in viral genes can negatively impact viral fitness.

Purpose of the Study:

• To investigate the impact of transgene codon usage on viral replication and oncolytic activity.
• To determine optimal codon strategies for enhancing oncolytic adenovirus efficacy.
• To guide the rational design of improved oncolytic virotherapies.

Main Methods:

• Analysis of transgene codon usage in oncolytic adenoviruses.
• Assessment of viral replication and transgene expression levels.
• Evaluation of in vitro and in vivo oncolytic activity.

Main Results:

• Optimized codons lead to high initial transgene expression but impair viral fitness and sustained expression.
• Suboptimal codons do not compromise viral replication, enabling stable transgene expression.
• Suboptimal codon usage results in enhanced oncolytic activity both in vitro and in vivo.

Conclusions:

• Fine-tuning codon usage is crucial for balancing transgene expression and viral replication.
• Suboptimal codon strategies offer a promising approach for developing more efficacious oncolytic adenoviruses.
• This study provides a rational design principle for next-generation oncolytic virotherapies.