A-L-B Agents Modulate Gene Expression via Brd4 Binding
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Solution Overview
Problem
Current treatments lack effective methods to modulate gene expression for diseases caused by expanded oligonucleotide repeat sequences, such as Friedreich's ataxia, Fragile X syndrome, Fragile X-associated tremor/ataxia syndrome, myotonic dystrophy type 1, and myotonic dystrophy type 2, which are characterized by transcriptional repression and reduced protein levels due to hyper-expansion of sequences like GAA, CGG, CTG, and CCTG repeats.
Innovation Solution
Development of 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 polyamide that specifically binds to oligonucleotide repeats, specifically targeting GAA, CGG, CTG, or CCTG sequences to increase mRNA and protein levels by stimulating transcriptional elongation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If expanded oligonucleotide repeat sequences are present in the genome, then gene transcription is repressed and protein levels are reduced, but no effective treatment method exists to modulate gene expression
Solution Approach 1:
The patent employs small molecule compounds as intermediaries that bind to expanded oligonucleotide repeat sequences and modulate transcriptional repression. These compounds act as mediators between the repeat sequences and the transcriptional machinery, specifically targeting the pausing of RNA polymerase-II to restore transcriptional elongation and increase protein expression levels.
2Productivity
If RNA polymerase-II pausing occurs at genes with expanded repeats, then transcriptional elongation is inhibited, but current therapies cannot effectively stimulate elongation
Solution Approach 1:
The patent utilizes small molecule compounds that change the physical-chemical parameters of the transcriptional complex by binding to expanded repeat sequences. This binding alters the conformational state of RNA polymerase-II and associated factors, facilitating the transition from a paused to an elongating state, thereby increasing transcriptional productivity.
3Quantity of substance
If hyper-expansion of oligonucleotide repeats occurs, then mRNA and protein levels decrease, but no specific therapy has been approved to prevent progression
Solution Approach 1:
The patent employs compounds that act preliminarily to prevent disease progression by restoring gene expression before significant neuronal damage occurs. The small molecules bind to repeat sequences and prevent the full establishment of transcriptional repression, thereby maintaining higher mRNA and protein levels that can prevent or delay disease manifestation and progression.
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 mRNA and protein levels in cells derived from patients with these conditions, potentially ameliorating symptoms by restoring gene expression to near-wild-type levels, as demonstrated by up to an 8-fold increase in frataxin mRNA levels in Friedreich's ataxia patient cells within 24 hours.
Implementation Method 1
B is a polyamide that specifically binds to oligonucleotide repeats, specifically targeting GAA, CGG, CTG, or CCTG sequences
Implementation Method 2
A is a Brd4 binding moiety; stimulating transcriptional elongation
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.