CRISPR/Cas9 TTR Gene Editing for ATTR Amyloidosis
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Solution Overview
Problem
Current treatments for ATTR amyloidosis, caused by pathogenic variants of the transthyretin (TTR) protein, do not effectively halt disease progression or improve quality of life, with existing therapies like small molecule stabilizers only slowing progression and liver transplantation involving significant risks.
Innovation Solution
The use of a guide RNA with an RNA-guided DNA binding agent, such as the CRISPR/Cas system, to specifically target and reduce or eliminate the production of the TTR protein by modifying the TTR gene, thereby reducing or eliminating the production of the TTR protein associated with ATTR amyloidosis.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If small molecule stabilizers are used to treat ATTR amyloidosis, then disease progression is slowed, but the treatment does not halt progression and quality of life remains compromised
Solution Approach 1:
The patent changes the fundamental parameter of TTR protein stability by using CRISPR/Cas9 gene editing to modify the TTR gene sequence itself, rather than using small molecule stabilizers that only temporarily slow progression. This genetic modification approach aims to fundamentally alter the protein's properties to prevent amyloid formation, thereby both halting disease progression and improving quality of life
2Reliability
If liver transplantation is performed to treat ATTR amyloidosis, then TTR production is reduced, but significant surgical risks are involved
Solution Approach 1:
The patent replaces the mechanical/surgical approach of liver transplantation with a molecular biology approach using CRISPR/Cas9 gene editing. Instead of physically removing and replacing the liver organ, the invention uses RNA-guided DNA binding agents to precisely edit the TTR gene in situ, thereby reducing TTR production while avoiding surgical risks entirely
3Duration of action of stationary object
If CRISPR/Cas9 gene editing is used to eliminate TTR production, then long-term reduction of TTR protein is achieved, but off-target effects and immune responses may occur
Solution Approach 1:
The patent uses guide RNA as an intermediary component that directs the Cas9 nuclease to the specific TTR gene target sequence. This RNA-mediated targeting system provides high specificity, reducing off-target effects. Additionally, the use of transient transfection or self-limiting viral vectors as delivery mechanisms limits the duration of Cas9 expression, thereby reducing immune response risks while maintaining long-term TTR reduction through permanent gene editing
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
This approach achieves a long-term reduction or elimination of TTR protein production, potentially halting disease progression and improving quality of life for patients with ATTR amyloidosis by reducing TTR serum concentration and preventing amyloid accumulation.
Implementation Method 1
a guide RNA with an RNA-guided DNA binding agent, such as the CRISPR/Cas system, to specifically target and reduce or eliminate the production of the TTR protein by modifying the TTR gene
Implementation Method 2
The use of a guide RNA with an RNA-guided DNA binding agent, such as the CRISPR/Cas system, to specifically target and reduce or eliminate the production of the TTR protein by modifying the TTR gene
Data Source
AI summary
Compositions and methods for editing, e.g., introducing double-stranded breaks, within the TTR gene are provided. Compositions and methods for treating subjects having amyloidosis associated with transthyretin (ATTR), are provided.