Histone Stem-Loop and Poly(A) Sequence for Higher Antigen Expression
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Solution Overview
Problem
Existing gene therapy and genetic vaccination methods face challenges in achieving sufficient mRNA stability and translational efficiency, leading to suboptimal expression of encoded proteins, particularly in the context of treating infectious diseases.
Innovation Solution
A nucleic acid sequence comprising a coding region for a pathogenic antigen, a histone stem-loop, and a poly(A) sequence or polyadenylation signal is used to enhance protein expression, leveraging a synergistic effect between these elements to stabilize and increase translation efficiency.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If traditional vaccination methods using live attenuated or heat-killed pathogens are used, then effective immune responses can be achieved against specific antigens, but major diseases like malaria and HIV still lack effective vaccines and existing vaccines provide only transient or partial protection
Solution Approach 1:
The invention segments the vaccine approach by targeting specific pathogenic antigens rather than using whole pathogens. The nucleic acid sequences encode specific antigenic peptides that can be independently selected and optimized for different pathogens, enabling tailored vaccine responses for diverse diseases including malaria and HIV.
Solution Approach 2:
The invention changes the fundamental parameter of vaccine delivery from traditional protein-based or pathogen-based approaches to nucleic acid-based delivery. This allows for optimized expression of antigenic peptides with controlled stability and translational efficiency, improving reliability while maintaining adaptability across different pathogen types.
2Productivity
If nucleic acid sequences are used for genetic vaccination, then expression of encoded proteins can be achieved, but mRNA stability and translational efficiency are insufficient leading to suboptimal protein expression
Solution Approach 1:
The invention merges multiple functional elements into a single nucleic acid sequence: the coding region for pathogenic antigen, a histone stem-loop structure for enhanced stability, and a poly(A) sequence for translational efficiency. This combination produces synergistic effects that simultaneously improve mRNA stability and protein expression levels.
Solution Approach 2:
The nucleic acid sequence functions as a composite molecular structure integrating different functional domains: the coding region provides antigenic information, the histone stem-loop provides structural stability, and the poly(A) sequence provides translational enhancement. This composite design achieves superior protein expression compared to individual elements alone.
3Ease of manufacture
If nucleic acid sequences without stabilizing elements are used, then simplicity of the sequence is maintained, but protein expression levels remain suboptimal for therapeutic applications
Solution Approach 1:
The invention modifies specific parameters of the nucleic acid sequence by incorporating the histone stem-loop and poly(A) sequence. These parameter changes enhance mRNA stability and translational efficiency, thereby increasing protein expression levels while maintaining reasonable sequence simplicity for manufacturing.
Data Source
AI summary
The present invention relates to a nucleic acid sequence, comprising or coding for a coding region, encoding at least one peptide or protein comprising a pathogenic antigen or a fragment, variant or derivative thereof, at least one histone stem-loop and a poly(A) sequence or a polyadenylation signal. Furthermore the present invention provides the use of the nucleic acid for increasing the expression of said encoded peptide or protein. It also discloses its use for the preparation of a pharmaceutical composition, especially a vaccine, e.g. for use in the treatment of infectious diseases. The present invention further describes a method for increasing the expression of a peptide or protein comprising a pathogenic antigen or a fragment, variant or derivative thereof, using the nucleic acid comprising or coding for a histone stem-loop and a poly(A) sequence or a polyadenylation signal.