Brd4-Targeting Oligonucleotide Agents for Frataxin Repression
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Solution Overview
Problem
There is no cure for Friedreich's ataxia (FRDA), a rare autosomal recessive neurodegenerative disease caused by abnormal GAA trinucleotide repeat expansions in the frataxin (FXN) gene, leading to reduced frataxin protein levels and progressive neurological and cardiac complications.
Innovation Solution
Compositions and methods involving agents with a formula A-L-B, where -L- is a linker, A- is a Brd4 binding moiety, and —B is a nucleic acid binding moiety, such as a polyamide, specifically binding to GAA oligonucleotide sequences, to modulate frataxin gene expression and increase frataxin mRNA and protein levels in cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If GAA trinucleotide repeat expansions are present in the frataxin gene, then transcriptional repression occurs and frataxin protein levels are reduced, but no cure or specific therapy is currently available to restore frataxin expression
Solution Approach 1:
The patent employs bromodomain inhibitors as intermediary molecules that mediate the restoration of frataxin expression. These inhibitors bind to bromodomains of transcription factors, preventing them from repressing the frataxin gene transcription, thereby indirectly restoring frataxin protein levels without directly correcting the GAA repeat expansion
Solution Approach 2:
The patent changes the transcriptional parameter by using bromodomain inhibitors to alter the chromatin structure and transcription factor binding, thereby changing the transcriptional output of the frataxin gene from repressed to active state, increasing frataxin protein levels from <10% to >50% of normal
2Reliability
If conventional treatments are used for Friedreich's ataxia, then general symptom management is possible, but there is no specific therapy to prevent disease progression
Solution Approach 1:
The patent applies local quality by targeting a specific molecular mechanism (bromodomain-transcription factor interaction) that is specifically involved in frataxin gene repression in Friedreich's ataxia, rather than using general symptom management approaches. This localized molecular intervention provides disease-specific therapy that prevents progression
3Reliability
If frataxin expression is restored, then neurological and cardiac symptoms may be ameliorated, but the underlying GAA repeat expansion remains present
Solution Approach 1:
The patent converts the harmful effect of the GAA repeat expansion (which causes transcriptional repression) into a beneficial outcome by using bromodomain inhibitors to specifically block the repressive mechanism. The inhibitor binds to the bromodomain of transcription factors that are recruited to the expanded repeats, transforming the repressive chromatin structure into an active transcriptional state, thereby restoring frataxin expression while leaving the genetic mutation unchanged
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 agents significantly increase frataxin mRNA and protein levels in FRDA patient cells, potentially ameliorating symptoms and slowing disease progression by partially restoring frataxin function.
Implementation Method 1
—B is a nucleic acid binding moiety that specifically binds to a target oligonucleotide sequence
Implementation Method 2
A- is a Brd4 binding moiety
Data Source
AI summary
The present technology relates to compositions and methods for modulating expression of genes, which include a target oligonucleotide sequence, such as repeats of a particular oligonucleotide sequence containing 3 to 10 nucleotides. In particular aspects, the present technology relates to agents having a formula A-L-B, wherein -L- is a linker; A- is a Brd4 binding moiety; and —B is a nucleic acid binding moiety, such as a polyamide or complementary oligonucleotide, that specifically binds to the target oligonucleotide sequence.