HBV Epigenetic Editing With Targeted DNA Methylation Silencing
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Solution Overview
Problem
Current treatments for chronic hepatitis B (CHB) have a low functional cure rate, with less than 20% achieving durable HBsAg loss and undetectable serum HBV after treatment, highlighting a need for improved therapeutic modalities targeting HBV.
Innovation Solution
Employing an epigenetic editing system comprising a DNA binding domain, a DNMT domain, and a transcriptional repressor domain to modify the HBV gene or genome, reducing HBV viral episomes, replication, and protein expression by at least 20% to 99.9% through targeted binding and methylation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current approved CHB therapies are used, then treatment is provided, but functional cure rate remains less than 20%
Solution Approach 1:
The invention changes the therapeutic approach from antiviral inhibition to epigenetic modification. By using DNA methyltransferase domains to add methyl groups to HBV DNA and histone modification domains to alter chromatin structure, the system fundamentally changes the epigenetic state of the virus, achieving durable silencing with functional cure rates exceeding 20% in preclinical models
Solution Approach 2:
The invention replaces the mechanical/enzymatic system of antiviral drugs that inhibit viral replication enzymes with an epigenetic system using fusion proteins containing DNA methyltransferase and histone modification domains. This substitution targets the host cell's epigenetic machinery to silence HBV gene expression, achieving more durable and complete suppression of viral antigens
2Productivity
If epigenetic editing system is administered, then HBV viral episomes and replication are reduced by up to 99.9%, but device complexity increases
Solution Approach 1:
The invention merges multiple functional domains into single fusion proteins: DNA binding domains (such as dCas9 or zinc finger proteins) are combined with DNA methyltransferase domains (DNMT3A, DNMT3L) and/or histone modification domains (such as HDACs or HATs). This consolidation achieves multi-functional epigenetic editing while simplifying delivery compared to separate protein components
Solution Approach 2:
The invention uses guide RNAs as intermediaries to direct the epigenetic editing fusion proteins to specific HBV DNA sequences. The guide RNA mediates between the programmable DNA binding domain and the target viral genome, enabling precise targeting without requiring complex protein-protein recognition systems
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 epigenetic editing system significantly reduces HBV viral episomes, replication, and protein expression by up to 99.9%, providing a more effective treatment for chronic hepatitis B.
Implementation Method 1
a first DNMT domain, wherein the first DNMT domain methylates a first target region of the HBV genome
Implementation Method 2
a transcriptional repressor domain, wherein the transcriptional repressor domain represses transcription of the HBV genome
Implementation Method 3
a first DNA binding domain, wherein the first DNA binding domain binds a first target region of the HBV genome
Data Source
AI summary
This invention relates to compositions, methods, strategies, and treatment modalities related to the epigenetic modification of hepatitis B virus (HBV) genes.