Oligonucleotide Combination for HBV cccDNA Destabilization
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Solution Overview
Problem
Current treatments for chronic hepatitis B virus (HBV) infection do not effectively target covalently closed circular DNA (cccDNA), which persists in the nucleus and serves as a template for viral transcription, leading to incomplete clearance of the virus.
Innovation Solution
A combination of RTEL1 and FUBP1 inhibitors, administered as oligonucleotides complementary to RTEL1 and FUBP1, is used to modulate their expression and activity, specifically targeting and destabilizing HBV cccDNA, thereby enhancing the treatment and prevention of HBV infection.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current treatments (nucleos(t)ide analogues or interferons) are used to treat chronic HBV infection, then viral replication is suppressed and HBsAg levels decrease, but cccDNA persists in the nucleus and serves as a template for viral transcription, leading to incomplete clearance of the virus
Solution Approach 1:
The patent extracts and targets the specific harmful component (cccDNA) that persists despite conventional treatment. By using oligonucleotides designed to bind specifically to cccDNA and the RTEL1-FUBP1 complex, the treatment removes or destabilizes this persistent viral reservoir, addressing the root cause of incomplete viral clearance that conventional therapies fail to eliminate
Solution Approach 2:
The patent introduces oligonucleotides as intermediary molecules that mediate between the host cellular machinery (RTEL1-FUBP1 complex) and the viral cccDNA. These oligonucleotides act as guides to recruit the RTEL1-FUBP1 complex to specific sites on cccDNA, enabling targeted destabilization of the viral genome without directly damaging the host cell
2Reliability
If a combination of RTEL1 and FUBP1 inhibitors is used to target and destabilize cccDNA, then synergistic inhibition of HBV is achieved and cccDNA levels are reduced, but the complexity of the treatment regimen increases
Solution Approach 1:
The patent merges two therapeutic agents (RTEL1 inhibitor and FUBP1 inhibitor) into a single combination treatment that targets the same molecular complex (RTEL1-FUBP1). This synergistic combination approach allows both agents to work together on the same pathway, achieving enhanced cccDNA destabilization while maintaining a relatively streamlined treatment regimen compared to targeting multiple unrelated pathways
Solution Approach 2:
The patent employs oligonucleotides that serve multiple functions: they act as inhibitors of RTEL1 or FUBP1, serve as guides to recruit the RTEL1-FUBP1 complex to cccDNA, and directly bind to destabilize cccDNA structure. This multi-functionality reduces the need for separate therapeutic agents for each mechanism, simplifying the overall treatment complexity
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 combination of RTEL1 and FUBP1 inhibitors demonstrates synergistic inhibition of HBV, effectively reducing cccDNA levels and improving treatment outcomes for chronic HBV infection by targeting the persistent viral template.
Implementation Method 1
oligonucleotides (oligomers) that are complementary to RTEL1 or FUBP1, respectively
Data Source
AI summary
The present invention relates to combinations of Regulator of telomere elongation helicase 1 (RTEL1) and Far Upstream Element-Binding Protein 1 (FUBP1) inhibitors, such as oligonucleotides (oligomers) that are complementary to RTEL1 or FUBP1, respectively, leading to modulation of the expression of RTEL1 and FUBP1 or modulation of RTEL1 and FUBP1 activity. The invention in particular relates to a combination of an inhibitor of RTEL1 and an inhibitor of FUBP1 for use in treating and/or preventing a disease, preferably a hepatitis B virus (HBV) infection, in particular a chronic HBV infection. The invention in particular relates to the use of a combination of RTEL1 and FUBP1 inhibitors for destabilizing cccDNA, such as HBV cccDNA. Also comprised in the present invention is a pharmaceutical composition, a kit and the use thereof in the treatment and/or prevention of a HBV infection.