Antisense Oligonucleotides Targeting MAPT Pre-mRNA for Tau Reduction
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Solution Overview
Problem
Current treatments for neurodegenerative disorders associated with Tau protein, such as Alzheimer's disease and Tauopathies, are inadequate, and there is a need for effective agents that can modulate Tau expression to prevent or treat these conditions.
Innovation Solution
The development of antisense oligonucleotides that target specific regions of the MAPT pre-mRNA, including positions 12051-12111, 39562-39593, and 72837-72940, to reduce Tau expression by cleavage of target nucleic acids via nuclease recruitment.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current treatments are used for neurodegenerative disorders, then existing therapy options are maintained, but treatment effectiveness is inadequate
Solution Approach 1:
The invention changes the therapeutic parameter from symptomatic management to targeted gene expression modulation. Antisense oligonucleotides are designed to specifically bind to MAPT pre-mRNA at defined sequences, altering the molecular parameter of Tau protein production at its source, thereby improving treatment reliability for neurodegenerative disorders
Solution Approach 2:
The antisense oligonucleotide acts as an intermediary molecule between the therapeutic agent and the target gene. It mediates the reduction of Tau expression by binding to specific sequences in MAPT pre-mRNA, enabling targeted intervention without directly modifying the gene itself, thus providing versatile therapeutic approach
2Reliability
If antisense oligonucleotides target specific MAPT pre-mRNA regions, then Tau expression is reduced, but manufacturing and delivery complexity increases
Solution Approach 1:
The invention segments the MAPT pre-mRNA into specific targetable regions with defined sequences. By identifying discrete sequences at defined positions in the pre-mRNA, the oligonucleotide design can focus on targeted segments rather than the entire transcript, reducing design complexity while maintaining effective Tau expression reduction
Solution Approach 2:
The invention applies local quality by designing oligonucleotides with specific sequence complementarity to particular regions of MAPT pre-mRNA. The oligonucleotides possess localized binding properties that match specific target sequences, enabling precise Tau expression reduction without requiring complex genome-wide modifications
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
These antisense oligonucleotides effectively reduce Tau protein levels both in vivo and in vitro, providing a potential therapeutic approach for neurodegenerative disorders associated with Tau expression.
Implementation Method 1
antisense oligonucleotides which reduce Tau both in vivo and in vitro... oligonucleotides targeting a Tau encoding nucleic acid which is capable of modulating the expression of Tau
Implementation Method 2
capable of inhibiting the expression of Tau by cleavage of a target nucleic acid. The cleavage is preferably achieved via nuclease recruitment
Data Source
AI summary
The present invention relates to antisense oligonucleotides that are capable of modulating expression of Tau in a target cell. The oligonucleotides hybridize to MAPT mRNA. The present invention further relates to conjugates of the oligonucleotide and pharmaceutical compositions and methods for treatment of Tauopathies, Alzheimzer's disease, fronto-temporal dementia (FTD), FTDP-17, progressive supranuclear palsy (PSP), chronic traumatic encephalopathy (CTE), corticobasal ganglionic degeneration (CBD), epilepsy, Dravet syndrome, depression, seizure disorders and movement disorders.