Modified Oligonucleotides for SNCA mRNA Suppression
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Solution Overview
Problem
Current treatments for neurodegenerative diseases such as Parkinson's disease, dementia with Lewy bodies, diffuse Lewy body disease, pure autonomic failure, multiple system atrophy, neuronopathic Gaucher's disease, and Alzheimer's disease are lacking effective options to reduce alpha-synuclein (SNCA) expression and associated symptoms.
Innovation Solution
Development of oligomeric compounds comprising modified oligonucleotides with specific nucleobase sequences and sugar motifs, including phosphorothioate internucleoside linkages, to reduce SNCA mRNA and protein levels, thereby ameliorating symptoms like motor dysfunction, aggregation, neurodegeneration, and cognitive decline.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional treatments are used for neurodegenerative diseases, then current therapeutic options are limited, but alpha-synuclein expression remains uncontrolled leading to disease progression
Solution Approach 1:
The patent applies parameter changes by modifying the chemical structure of oligonucleotide compounds through various sugar motifs (2'-O-methoxyethyl, 2'-deoxyribose, morpholino rings) and internucleoside linkages (phosphorothioate, phosphodiester, methylphosphonate) to optimize both therapeutic effectiveness and stability for treating neurodegenerative diseases
Solution Approach 2:
The patent employs composite materials by creating chimeric oligonucleotide structures that combine multiple nucleoside types with different sugar motifs and linkages in a single molecule, thereby achieving both high affinity binding to SNCA mRNA and resistance to nucleolytic degradation
2Quantity of substance
If alpha-synuclein expression is reduced using modified oligonucleotides, then SNCA mRNA and protein levels decrease, but the complexity of the compound structure increases
Solution Approach 1:
The patent applies segmentation by dividing the oligonucleotide into distinct functional regions: 5' wing nucleosides with modified sugars for stability, central gap region with unmodified 2'-deoxyribose for RNase H recruitment, and 3' wing nucleosides for extended binding, thereby managing structural complexity through functional modularization
Solution Approach 2:
The patent applies local quality by applying different sugar modifications to different regions of the oligonucleotide - 2'-O-methoxyethyl at terminal positions for stability, unmodified 2'-deoxyribose in the central region for enzymatic recognition, and phosphorothioate linkages at specific positions for enhanced nuclease resistance, optimizing each region for its specific function
Data Source
AI summary
Provided are compounds, methods, and pharmaceutical compositions for reducing the amount or activity of SNCA mRNA in a cell or animal, and in certain instances reducing the amount of alpha-synuclein protein in a cell or animal. Such compounds, methods, and pharmaceutical compositions are useful to ameliorate at least one symptom or hallmark of a neurodegenerative disease. Such symptoms and hallmarks include motor dysfunction, aggregation of alpha-synuclein, neurodegeneration, cognitive decline and dementia. Such neurodegenerative diseases include Parkinson's disease, dementia with Lewy bodies, diffuse Lewy body disease, pure autonomic failure, multiple system atrophy, neuronopathic Gaucher's disease and Alzheimer's disease.