Engineered Latent Guide RNAs for LRRK2 RNA Editing
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Solution Overview
Problem
Current technologies lack an effective method for specifically editing adenosine in LRRK2 RNA, which is crucial for treating diseases associated with mutations in the LRRK2 polypeptide.
Innovation Solution
Engineered latent guide RNAs that, upon hybridization to LRRK2 RNA, form guide-target RNA scaffolds with specific structural features like mismatches, bulges, internal loops, and hairpins, facilitating targeted RNA editing by RNA editing entities such as ADAR1 and ADAR2.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Manufacturing precision
If conventional guide RNAs are used for RNA editing, then the editing process can proceed, but the specificity and efficiency of adenosine editing in LRRK2 RNA is insufficient
Solution Approach 1:
The guide RNA is engineered with specific local structural features including a mismatch at position +1 relative to the target adenosine, and internal loops at positions -14 to -16 and +22 to +24. These localized structural modifications create a unique micro-footprint that significantly enhances both the specificity and efficiency of adenosine editing in LRRK2 RNA without affecting other regions of the RNA molecule.
2Stability of the object's composition
If the guide RNA sequence is highly complementary to the target RNA, then hybridization stability increases, but the formation of specific structural features like mismatches and internal loops becomes difficult
Solution Approach 1:
The guide RNA is pre-engineered with predetermined mismatch and internal loop positions in its sequence design. These structural features are built into the guide RNA molecule before hybridization occurs, ensuring that upon binding to the target LRRK2 RNA, the specific micro-footprint structure forms automatically. This preliminary structuring resolves the conflict between hybridization stability and structural feature formation.
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 engineered guide RNAs achieve high specificity and efficiency in editing the target adenosine in LRRK2 RNA, potentially leading to therapeutic interventions for diseases like Parkinson's and Crohn's.
Implementation Method 1
upon hybridization to a sequence of a target LRRK2 RNA, forms a guide-target RNA scaffold
Implementation Method 2
facilitates RNA editing of an on-target adenosine in the sequence of the target LRRK2 RNA by an RNA editing entity
Data Source
AI summary
Disclosed herein are engineered latent guide RNAs targeting LRRK2 and compositions comprising the same for treatment of diseases or conditions (e.g. Parkinson's Disease) in a subject. Also disclosed herein are methods of treating diseases or conditions (e.g. Parkinson's Disease) in a subject by administering engineered latent guide RNAs or pharmaceutical compositions described herein.