Histone Stem-Loop and Poly(A) Sequence for mRNA Stability

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Solution Overview

Problem

Current 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 cancer treatment where conventional therapies stress the immune system and require long recovery intervals.

Innovation Solution

A nucleic acid sequence comprising a coding region for a tumour-specific antigen or fragment, combined with a histone stem-loop and a poly(A) sequence or polyadenylation signal, enhances protein expression by synergistic action of these elements, regardless of their order or length, to improve mRNA stability and translational efficiency.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If conventional gene therapy and genetic vaccination methods are used, then mRNA can be introduced into cells, but mRNA stability is insufficient and translational efficiency is suboptimal

Engineering Contradiction:

ImprovemRNA stabilityVSAvoidprotein expression level

Core Design Contradiction:

ReliabilityVSProductivity

Solution Approach 1:

The patent combines a poly(A) sequence with a histone stem-loop structure to create a hybrid 3' end configuration. This merging of two distinct mRNA terminal structures (poly(A) tail and stem-loop) produces a synergistic effect that simultaneously enhances mRNA stability and translational efficiency, resolving the contradiction between reliability and productivity.

Inventive Principle:

Principle #5Merging (Combining)

Solution Approach 2:

The invention creates a composite mRNA structure by integrating multiple functional elements: the coding region, poly(A) sequence, and histone stem-loop. This composite design allows different parts of the mRNA molecule to perform specialized functions - the poly(A) sequence provides stability while the stem-loop enhances translation, achieving both improved reliability and productivity.

Inventive Principle:

Principle #40Composite materials

2Reliability

If conventional therapies (radiation therapy or chemotherapy) are used to treat cancer, then tumour treatment can be achieved, but the immune system experiences extraordinary stress and requires long recovery intervals

Engineering Contradiction:

Improvetumour treatment effectivenessVSAvoidimmune system recovery time

Core Design Contradiction:

ReliabilityVSDuration of action of moving object

Solution Approach 1:

The patent replaces conventional mechanical/chemical therapies (radiation and chemotherapy) with a molecular biology-based approach using engineered mRNA. This substitution enables tumour treatment through enhanced protein expression of tumour antigens, which triggers immune response without the severe stress on the immune system caused by conventional methods, thereby reducing recovery time.

Inventive Principle:

Principle #28Mechanics substitution (Replace mechanical system)

Solution Approach 2:

The engineered mRNA acts as an intermediary that delivers tumour antigen information to cells without directly killing tumour cells. This indirect approach through mRNA-mediated protein expression allows the immune system to respond to tumour antigens while avoiding the direct cytotoxic effects of conventional therapies, reducing immune system stress and recovery time.

Inventive Principle:

Principle #24Intermediary (Mediator)

3Productivity

If mRNA is used for gene therapy, then protein expression can be achieved, but RNA is chemically more labile than DNA and RNases are ubiquitous

Engineering Contradiction:

Improveprotein expressionVSAvoidmRNA stability

Core Design Contradiction:

ProductivityVSStability of the object's composition

Solution Approach 1:

The patent incorporates protective elements (poly(A) sequence and histone stem-loop structure) at the 3' end of the mRNA molecule before degradation can occur. These structural features act as a protective cushion that prevents RNase access and stabilizes the mRNA against chemical degradation, thereby maintaining mRNA integrity while preserving protein expression capability.

Inventive Principle:

Principle #11Beforehand cushioning (Prior cushioning)

Solution Approach 2:

The patent creates a protective structural shell around the mRNA molecule through the formation of the stem-loop structure and poly(A) tail. This structural envelope protects the labile RNA from enzymatic degradation by RNases and chemical attacks, enhancing mRNA stability while maintaining its functional properties for protein expression.

Inventive Principle:

Principle #30Flexible shells and thin films

Data Source

PatentEP3527662B1Nucleic acid comprising or coding for a histone stem-loop and a poly(a) sequence or a polyadenylation signal for increasing the expression of an encoded tumour antigen

Publication Date: 2022.01.26 CUREVAC SE

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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 tumour 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 cancer or tumour diseases. The present invention further describes a method for increasing the expression of a peptide or protein comprising a tumour 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.