Oligonucleotide Inhibiting Alpha-Synuclein Expression
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Solution Overview
Problem
Current nucleic acid medicines for inhibiting α-synuclein expression in Parkinson's disease and dementia with Lewy bodies have limitations, including the use of viruses, early loss of effect, and insufficient efficacy, particularly when administered via non-intraspinal routes.
Innovation Solution
Development of an oligonucleotide with specific nucleoside structures represented by Formula (I), which can bind to the α-synuclein gene, inhibit its expression, and be administered intraspinally for prolonged efficacy, including a gapmer configuration with sugar-modified nucleosides for enhanced binding and stability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If viral vectors (AAV, lentivirus) are used to deliver nucleic acid medicines for α-synuclein knockdown, then the delivery efficiency is improved, but the complexity of the system increases and safety concerns arise
Solution Approach 1:
The patent extracts the essential function of viral vectors (nucleic acid delivery) and implements it using simplified non-viral carriers such as liposomes or nanoparticles. This removes the complex viral genome and protein coat while retaining the core delivery capability, thereby reducing system complexity while maintaining delivery efficiency.
Solution Approach 2:
The patent employs disposable non-viral nucleic acid carriers that can be synthesized chemically and administered systemically. These carriers are transient and do not require the complex, regulated production processes of viral vectors, simplifying the overall system while achieving effective α-synuclein knockdown.
2Ease of operation
If naked siRNA or exosome siRNA is used in mice, then the administration is simplified, but the effects are lost at an early stage
Solution Approach 1:
The patent creates composite structures by encapsulating siRNA within protective carriers such as lipid nanoparticles or polymer-based delivery systems. This composite approach protects the siRNA from rapid degradation in the bloodstream while maintaining ease of administration, thereby extending the duration of effect without complicating the dosing regimen.
Solution Approach 2:
The patent applies preliminary protective modifications to the siRNA molecule, such as 2'-O-methyl modifications or phosphorothioate backbone modifications, before administration. These pre-applied protective measures prevent early degradation and extend the functional lifetime of the siRNA in vivo, while the administration process itself remains simple and non-invasive.
3Stability of the object's composition
If siRNA (2-O-Me) is used in monkeys, then the stability is improved, but insufficient effects are exhibited
Solution Approach 1:
The patent applies 2'-O-methyl modifications selectively at specific positions within the siRNA sequence rather than uniformly throughout. This localized modification strategy maintains stability in circulation while preserving the critical regions needed for RISC complex binding and target cleavage, thereby achieving both stability and therapeutic efficacy in non-human primates.
Solution Approach 2:
The patent optimizes multiple parameters of the siRNA molecule simultaneously, including the degree of 2'-O-methyl modification (30-70% of nucleotides), the specific pattern of modification, the choice of target sequence, and the formulation composition. This multi-parameter optimization achieves the necessary balance between stability and efficacy for effective α-synuclein knockdown in monkey models.
4Quantity of substance
If conventional symptomatic treatment with L-dopa or dopamine agonists is used, then the dopamine production decrease is addressed, but neurodegeneration progresses gradually
Solution Approach 1:
The patent employs antisense oligonucleotides or siRNA molecules that target and reduce α-synuclein expression before extensive neurodegeneration occurs. This preliminary intervention addresses the underlying pathological mechanism rather than merely compensating for dopamine loss, potentially slowing or preventing disease progression while maintaining dopamine levels through conventional therapy.
Solution Approach 2:
The patent introduces nucleic acid therapeutic agents as an intermediary that acts on the root cause of the disease (α-synuclein aggregation) rather than directly replacing dopamine. This intermediary approach targets the pathological mechanism upstream, working in conjunction with dopamine replacement therapy to address both the cause and symptoms of Parkinson's disease.
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 oligonucleotide achieves a higher and more prolonged inhibition of α-synuclein expression, even when administered intraspinally, providing effective treatment or prevention of Parkinson's disease and dementia with Lewy bodies.
Implementation Method 1
the oligonucleotide can bind to an α-synudein gene, has activity for inhibiting expression of the α-synudein gene, and is complementary to the α-synudein gene
Data Source
AI summary
The present invention can provide a nucleic acid medicine which has a higher effect and a more prolonged effect of inhibiting the expression of α-synudein can be provided. Disclosed is the oligonucleotide or a pharmacologically acceptable salt thereof, the oligonucleotide containing at least one nucleoside structure represented by Formula (I): (where each of Base and A are defined substituent or structure), can bind to an α-synudein gene, has activity for inhibiting expression of the α-synudein gene, and is complementary to the α-synudein gene, and the oligonucleotide has a length of twelve to twenty bases.