RNAi Agent Targeting RPS25 for Nucleotide Repeat Expansion
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Solution Overview
Problem
Current treatments lack efficacy for nucleotide repeat expansion diseases such as C9orf72 ALS/FTD and Huntington's disease, with no disease-modifying therapies available, relying on supportive and symptomatic management.
Innovation Solution
Development of RNAi agent compositions that target and inhibit the expression of the small ribosomal protein subunit 25 (RPS25) gene through RNA-induced silencing complex (RISC)-mediated cleavage, using double-stranded RNAi agents with specific sense and antisense strands to reduce RPS25 gene expression.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If supportive and symptomatic management is used for nucleotide repeat expansion diseases, then patient care is provided, but disease progression cannot be modified
Solution Approach 1:
The patent extracts and targets the specific RPS25 gene expression that drives RAN translation in nucleotide repeat expansion diseases. By designing RNAi agents that specifically bind to RPS25 mRNA, the invention isolates and suppresses only the problematic gene expression while leaving other cellular functions intact, thereby achieving disease modification without global translation inhibition
Solution Approach 2:
The patent introduces RNAi agents as intermediary molecules that mediate between the therapeutic goal (inhibiting RPS25) and the molecular target (RPS25 mRNA). These agents include siRNA, shRNA, and antisense oligonucleotides that serve as intermediaries to trigger RISC-mediated cleavage of RPS25 transcripts, converting the therapeutic intent into specific molecular action
2Reliability
If RNAi agents are designed to inhibit RPS25 gene expression, then therapeutic effect is achieved, but specificity of targeting must be maintained
Solution Approach 1:
The patent applies local quality by designing RNAi agents with specific nucleotide sequences that are complementary only to RPS25 mRNA target sites. The agents incorporate modified nucleotides (2'-O-methyl, 2'-fluoro) at specific positions to enhance binding affinity and specificity for the intended target while minimizing off-target effects, thereby achieving therapeutic efficacy with high precision
Solution Approach 2:
The patent employs composite RNAi agent compositions that combine multiple elements: sense and antisense strands with specific sequences, modified nucleotides for stability and specificity, and controlled secondary structures. These composite structures integrate different functional properties (binding affinity, specificity, stability) into a single therapeutic agent that can effectively inhibit RPS25 while maintaining manageable complexity
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 RNAi agents effectively inhibit RPS25 gene expression, potentially providing a therapeutic approach for nucleotide repeat expansion diseases by targeting the underlying cause of these conditions.
Implementation Method 1
RNAi agent compositions which effect the RNA-induced silencing complex (RISC)-mediated cleavage of RNA transcripts of a small ribosomal protein subunit 25 (RPS25) gene
Implementation Method 2
The RPS25 gene may be within a cell, e.g., a cell within a subject, such as a human. The present disclosure also provides methods of using the RNAi agent compositions of the disclosure for inhibiting the expression of an RPS25 gene
Data Source
AI summary
The disclosure relates to double stranded ribonucleic acid (dsRNAi) agents and compositions targeting an RPS25 gene, as well as methods of inhibiting expression of an RPS25 gene and methods of treating subjects having an RPS25-associated disease or disorder, such as a nucleotide repeat expansion disorder, e.g., c9orf72 amyotrophic lateral sclerosis (ALS)/frontotemporal demential (FTD) and Huntington-Like Syndrome Due To C9orf72 Expansions, using such dsRNAi agents and compositions.