Nucleoside Agents Targeting Extended Nucleotide Repeat Genes
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Solution Overview
Problem
Current methods fail to effectively reduce the deleterious activity of mutant extended nucleotide repeat-containing genes, which contribute to various diseases by producing toxic RNA or proteins, leading to cellular toxicity and dysfunction.
Innovation Solution
The use of nucleoside agents that contact cells to selectively reduce the production or activity of toxic expression products encoded by these genes, such as by inhibiting the Spt4 protein complex involved in transcription elongation through long trinucleotide repeat domains, thereby modulating protein expression and activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Object-affected harmful factors
If current methods are used to address mutant extended nucleotide repeat-containing genes, then general gene suppression approaches are applied, but non-selective suppression of both mutant and normal genes occurs, leading to loss of normal gene function
Solution Approach 1:
The nucleoside agent selectively targets transcription elongation through extended trinucleotide repeat domains, affecting only mutant genes with expanded repeats while sparing normal genes with intact sequences. This local quality differentiation allows selective suppression of toxic products without compromising normal gene function.
Solution Approach 2:
The invention exploits the parameter difference in repeat length between mutant and normal genes. The nucleoside agent's ability to inhibit transcription elongation is specifically triggered by the presence of extended trinucleotide repeats (pathogenic threshold), creating a parameter-based selectivity that distinguishes mutant from normal alleles.
2Object-generated harmful factors
If general gene suppression is applied to reduce toxic products, then production of toxic RNA or protein decreases, but normal gene expression is also reduced, causing cellular dysfunction
Solution Approach 1:
The nucleoside agent exhibits local quality selectivity by targeting only the abnormal transcription elongation process through extended repeats, while leaving normal transcription unaffected. This ensures that toxic expression products are suppressed without reducing normal gene expression and cellular productivity.
3Object-generated harmful factors
If transcription elongation through long trinucleotide repeat domains is inhibited, then production of toxic proteins is reduced, but complete inhibition may stop all transcription including normal genes
Solution Approach 1:
The nucleoside agent's inhibitory effect is parameter-dependent on the length and structure of trinucleotide repeats. It selectively inhibits transcription elongation only when pathogenic repeat thresholds are exceeded, maintaining ease of operation through selective action rather than complete inhibition of all transcription.
4Object-affected harmful factors
If existing therapies are used for trinucleotide repeat disorders, then symptomatic relief may be achieved, but the underlying mechanism of toxic RNA and protein production is not addressed
Solution Approach 1:
The invention converts the harmful property of extended trinucleotide repeats into a selective target. The abnormal repeat structures that cause disease are transformed into the very feature that enables selective recognition and inhibition by the nucleoside agent, addressing the root mechanism rather than just symptoms.
Data Source
AI summary
Aspects of the invention include methods of reducing the deleterious activity of a mutant extended nucleotide repeat (NR) containing target gene in a cell by contacting the cell with an effective amount of a nucleoside agent, as well as compositions used in such methods. The deleterious activity (e.g., toxicity and/or dis-functionality of products encoded thereby) of a mutant extended NR containing target gene may be reduced in a variety of different ways, e.g., by reducing (and in some instances differentially, including selectively, reducing) the production or activity of toxic expression products (e.g., RNA or protein) encoded by the target gene. Kits and compositions for practicing the subject methods are also provided.