HBV Epigenetic Editing of Regulatory Regions Without DNA Breaks
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Solution Overview
Problem
Current treatments for hepatitis B virus (HBV) are unable to achieve a functional cure due to the persistence of covalently closed circular DNA (cccDNA) and integrated DNA in hepatocytes, leading to ongoing viral replication and protein expression, despite the use of nucleoside analogs and IFN, which require long-term medication and result in rebound replication upon cessation.
Innovation Solution
An epigenetic editing tool is developed to introduce inhibitory modifications into specific regulatory regions of the HBV genome using a fusion molecule comprising DNA binding proteins and gene expression modulators, guided by single guide RNA (sgRNA) to target and silence cccDNA and integrated DNA, thereby reducing viral replication and protein expression.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If nucleoside analogs and IFN are used to inhibit HBV replication, then viral replication is suppressed, but cccDNA and integrated DNA persist leading to rebound replication upon treatment cessation
Solution Approach 1:
The patent extracts and targets the specific problematic regions (CpG islands and regulatory elements) within the HBV genome for epigenetic modification, separating the treatment focus from the entire viral genome and concentrating on key regulatory regions that control viral replication and protein expression
Solution Approach 2:
The patent changes the epigenetic parameters (methylation status, histone modifications) of the HBV genome regulatory regions to transition the chromatin structure from active to repressed states, thereby silencing viral gene expression without eliminating the viral DNA
2Productivity
If conventional treatments are used to suppress HBV, then viral replication is reduced, but long-term medication is required and treatment cessation leads to replication rebound
Solution Approach 1:
The patent performs preliminary epigenetic programming of the HBV cccDNA and integrated DNA to establish a repressed chromatin state before treatment cessation, creating a pre-conditioned state that maintains viral silencing without requiring continuous medication
Solution Approach 2:
The epigenetic modifications create a self-sustaining repressed state of the viral genome that maintains itself without continuous external intervention, allowing the system to serve itself by maintaining viral silencing through stable epigenetic marks
3Object-affected harmful factors
If epigenetic editing is used to silence HBV genes, then viral replication and protein expression are reduced without DNA breaks, but the technology is still in early development stages
Solution Approach 1:
The patent uses epigenetic modifiers (DNA methyltransferases, histone modifiers) as intermediaries that indirectly regulate viral gene expression through chromatin structure changes, rather than directly cleaving DNA, thus avoiding the harmful effects of DNA breaks while achieving gene silencing
Data Source
AI summary
The present application relates to the field of biomedicine, and provides an epigenetic editing tool for targeting a hepatitis B virus gene and a use thereof.