Artificial Nucleic Acid Molecules With Optimized UTRs
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Solution Overview
Problem
Current nucleic acid-based therapies, such as gene therapy and immunotherapy, face challenges with inadequate uptake and expression of therapeutic nucleic acids in vivo, leading to limited clinical success due to inefficient delivery and transcription of therapeutic proteins or antigens, which hampers their practical application.
Innovation Solution
The use of artificial nucleic acid molecules comprising specific 5' and 3' untranslated regions (UTRs) derived from selected genes, which synergistically enhance the expression of operably linked nucleic acid sequences, enabling rapid and transient production of therapeutic peptides or proteins, thereby improving delivery and uptake efficacy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If viral vectors are used for gene delivery, then gene expression is improved, but safety and ethical issues arise
Solution Approach 1:
The patent employs non-integrating AAV vectors that temporarily express therapeutic genes without permanently altering host DNA, treating the genetic material as a transient carrier rather than a permanent modification. This approach maintains gene expression efficacy while eliminating the permanent safety risks associated with viral integration.
Solution Approach 2:
The patent uses AAV vectors as intermediary carriers that deliver therapeutic nucleic acids to target cells without integrating into the host genome. The vector serves as a temporary mediator that facilitates gene expression while avoiding direct modification of host DNA, thereby reducing safety concerns.
2Reliability
If retroviral vectors are used for gene delivery, then gene integration is achieved, but insertional mutagenesis and cancer risk increase
Solution Approach 1:
The patent adopts non-integrating AAV vectors that provide temporary gene expression without permanent genomic integration. This treats the therapeutic nucleic acid delivery as a transient process, eliminating the long-term cancer risks associated with retroviral integration while maintaining sufficient reliability for therapeutic applications.
Solution Approach 2:
The patent converts the potential harm of viral integration (which causes insertional mutagenesis) into a benefit by using non-integrating AAV vectors. These vectors achieve sufficient gene expression without the harmful integration side effects, turning a potentially dangerous mechanism into a safe therapeutic approach.
3Ease of manufacture
If non-viral DNA vectors are used for vaccine delivery, then ease of manufacture and storage is improved, but antigen expression and immune response are insufficient
Solution Approach 1:
The patent modifies the DNA vector parameters by incorporating optimized 5' and 3' UTR sequences from specific genes (HSD17B4, ASAH1, ATP5A1, MP68, NDUFA4, NOSIP, RPL31, SLC7A3, TUBB4B, UBQLN2 for 5' UTR; PSMB3, CASP1, COX6B1, GNAS, NDUFA1, RPS9 for 3' UTR). These parameter changes enhance transcriptional efficiency and antigen expression while maintaining the ease of manufacture and storage characteristics of non-viral DNA vectors.
Solution Approach 2:
The patent creates composite DNA vector structures combining coding sequences with optimized UTR elements from multiple genes. This composite approach synergistically enhances antigen expression while preserving the manufacturing and storage advantages of non-viral DNA delivery systems.
4Productivity
If electroporation is used for nucleic acid delivery, then cellular uptake is improved, but device complexity and patient compliance issues arise
Solution Approach 1:
The patent replaces the mechanical electroporation system with a chemical/biological approach using optimized DNA vector sequences. The enhanced 5' and 3' UTR elements naturally improve cellular uptake and transcription without requiring external electrical fields or complex delivery devices, thereby maintaining high productivity while eliminating device complexity.
5Productivity
If viral vectors are used for vaccine delivery, then immune response is improved, but anti-viral immune response and pathogenic infection risk increase
Solution Approach 1:
The patent uses non-integrating AAV vectors that provide temporary antigen expression without permanent genomic integration. This transient approach maintains immune response generation capability while avoiding the long-term risks of viral persistence and anti-viral immune responses, treating the viral vector as a disposable delivery mechanism rather than a permanent modification.
Data Source
AI summary
The present invention provides artificial nucleic acid molecules comprising novel combinations of 5′ and 3′ untranslated region (UTR) elements. The inventive nucleic acid molecules are preferably characterized by increased expression efficacies of coding regions operably linked to said UTR elements. The artificial nucleic acids can be used for treatment or prophylaxis of various diseases. The invention further provides (pharmaceutical) compositions, vaccines and kits comprising said artificial nucleic acid molecules. Further, in vitro methods for preparing artificial nucleic acid molecules according to the invention are provided.