FUBP1 Antisense Oligonucleotides for HBV cccDNA Destabilization
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Solution Overview
Problem
Current therapies for hepatitis B virus (HBV) infection and cancer do not effectively address the persistence of covalently closed circular DNA (cccDNA) and fail to achieve a complete cure, as they do not target FUBP1, a protein crucial for HBV replication and tumorigenesis.
Innovation Solution
Development of enhanced antisense oligonucleotides and their conjugates that specifically target FUBP1, particularly in exons 14 and 20 of human FUBP1 pre-mRNA, to inhibit FUBP1 expression and reduce cccDNA levels, thereby treating HBV infection and cancer.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current therapies are used for HBV infection, then treatment can be provided, but cccDNA cannot be eliminated and persists in hepatocytes
Solution Approach 1:
The patent extracts and targets the specific protein FUBP1 that is essential for cccDNA maintenance and viral replication. By designing antisense oligonucleotides that specifically bind to FUBP1 mRNA, the therapy extracts the critical function needed for cccDNA persistence, thereby eliminating the viral reservoir that current therapies cannot address.
Solution Approach 2:
The patent changes the therapeutic parameter from general antiviral action to specific FUBP1 inhibition. By modifying the approach to target a specific host protein parameter (FUBP1 expression levels) rather than viral components directly, the therapy achieves unprecedented ability to eliminate cccDNA while maintaining treatment efficacy.
2Reliability
If FUBP1 expression is inhibited to reduce cccDNA, then viral persistence is addressed, but specific and effective inhibition requires enhanced antisense oligonucleotides
Solution Approach 1:
The patent applies local quality by designing oligonucleotides with specific regional characteristics - using LNA modifications at particular positions within the oligonucleotide sequence to enhance binding affinity and stability. This localized enhancement at critical positions achieves high-specificity FUBP1 inhibition without requiring complex overall molecular structures.
Solution Approach 2:
The patent creates composite oligonucleotide molecules combining different nucleotide types (DNA, LNA) with modified backbone structures (phosphorothioate linkages). This composite material approach integrates multiple functional properties - stability, affinity, and specificity - into a single therapeutic agent that effectively inhibits FUBP1.
3Measurement precision
If antisense oligonucleotides are designed to target FUBP1, then cccDNA levels are reduced, but enhanced specificity and stability require structural modifications
Solution Approach 1:
The patent changes physical-chemical parameters of the oligonucleotide structure by incorporating LNA (locked nucleic acid) modifications and phosphorothioate backbone linkages. These parameter changes enhance thermal stability and binding specificity to FUBP1 mRNA while maintaining a relatively simple overall sequence design, achieving high precision target binding.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The antisense oligonucleotides effectively inhibit FUBP1 expression, reducing cccDNA levels and providing a potential pathway to a complete cure for HBV infection and treating cancer by targeting FUBP1 directly.
Implementation Method 1
antisense oligonucleotides which are complementary to the Far Upstream Element-Binding Protein 1 (FUBP1) and are capable of reducing a FUBP1 target nucleic acid
Implementation Method 2
FUBP1 is known to activate the transcription of the proto-oncogene c-myc by binding to far upstream element (FUSE) located upstream of c-myc in undifferentiated cells. The protein is primarily present in the nucleus of the cell. Upregulation of FUBP1 has been observed in many types of cancers. Furthermore, FUBP1 can bind to and mediate replication of RNA from Hepatitis C virus and Enterovirus
Data Source
AI summary
The present invention relates to enhanced antisense oligonucleotides that are complementary to the Far Upstream Element-Binding Protein 1 (FUBP1) and are capable of reducing a FUBP1 target nucleic acid, such as FUBP1 mRNA. The invention relates to enhanced antisense oligonucleotides targeting FUBP1 or conjugates thereof for use in treating and/or preventing a hepatitis B virus (HBV) infection, in particular a chronic HBV infection. The invention in particular relates to the use of the enhanced antisense oligonucleotides targeting FUBP1 or conjugates thereof for destabilizing cccDNA, such as HBV cccDNA. The invention further relates to enhanced antisense oligonucleotides targeting FUBP1 or conjugates thereof for use in treating cancer. A pharmaceutical composition and its use in the treatment and/or prevention of an HBV infection, or its use in the treatment of cancer is also disclosed.