HTT Gene Editing for Durable Huntington's Protein Suppression
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Solution Overview
Problem
Current treatments for Huntington's Disease (HD) are inadequate, as they require regular dosing and do not provide a permanent solution to halt huntingtin protein expression, and there is no therapy capable of altering the disease's course without re-dosing.
Innovation Solution
A CRISPR/Cas9-based gene editing system is used to target and edit the HTT gene, specifically through gRNAs that recognize and introduce double-strand breaks in exons of the HTT gene, reducing huntingtin protein expression by at least 50% using viral vectors like AAV for delivery to neurons and glial cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If RNA interference is used to halt huntingtin expression, then huntingtin protein expression is reduced, but regular re-dosing is required to maintain the effect
Solution Approach 1:
The CRISPR/Cas9 system performs preliminary genomic editing to permanently disrupt the HTT gene sequence, creating a lasting therapeutic effect that eliminates the need for repeated dosing. The gRNA and Cas9 enzyme are delivered once to achieve permanent gene modification, contrasting with RNA interference which requires continuous re-administration.
Solution Approach 2:
The invention changes the fundamental parameter of therapeutic duration by transitioning from transient RNA interference to permanent genomic editing. This parameter change transforms the treatment from requiring regular re-dosing to providing a single-intervention, long-lasting solution.
2Duration of action of moving object
If CRISPR/Cas9 system is used to permanently depress HTT gene activity, then a single intervention is sufficient, but delivery to neurons and glial cells must be achieved
Solution Approach 1:
Viral vectors serve as intermediaries to deliver the CRISPR/Cas9 system components into neurons and glial cells. The viral vector acts as a mediator that bridges the gap between the therapeutic agent and the target cells, enabling efficient delivery without direct injection of complex molecular components.
Solution Approach 2:
The CRISPR/Cas9 system is segmented into separate components (Cas9 enzyme, gRNA, and viral vector) that can be independently optimized and delivered. This segmentation allows the complex delivery challenge to be addressed through modular approaches, with each component serving a specific function in the delivery and editing process.
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 system effectively and permanently depresses huntingtin protein activity, offering a single-intervention therapy for HD by significantly reducing its expression in targeted cells.
Implementation Method 1
A CRISPR/Cas9-based gene editing system is used to target and edit the HTT gene, specifically through gRNAs that recognize and introduce double-strand breaks in exons of the HTT gene
Data Source
AI summary
The present disclosure provides methods and compositions concerning the CRISPR/Cas9 systems and associated guide RNAs, which target and excise portions of particular exons of a huntingtin gene, thereby abrogating huntingtin protein expression. The disclosure further provides methods and compositions for treating Huntington's Disease.