Antisense Oligonucleotides for Expanded Repeat Diseases
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Solution Overview
Problem
Current therapeutic options for expanded repeat diseases such as Huntington's disease and amyotrophic lateral sclerosis (ALS) are inadequate, as they do not effectively address the underlying molecular mechanisms or significantly alter disease progression.
Innovation Solution
Development of antisense oligonucleotides that specifically hybridize to mutant mRNA produced from expanded nucleotide repeat alleles, using sequences complementary to the expanded repeats, to reduce the expression of toxic proteins associated with these diseases.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If antisense oligonucleotides are designed to hybridize to expanded repeat sequences, then selectivity for mutant allele is improved, but risk of off-target effects increases
Solution Approach 1:
The patent applies local quality by designing oligonucleotides with chemically modified bases (e.g., 5-methylcytosine) at specific positions within the sequence, particularly at the 3' end, to enhance binding affinity and selectivity for the mutant allele while minimizing off-target effects. This localized modification strategy improves discrimination between mutant and wild-type alleles without requiring complete sequence alteration.
Solution Approach 2:
The patent employs parameter changes by systematically varying oligonucleotide characteristics including length (15-50 nucleotides), chemical composition (DNA, RNA, LNA, PNA backbones), charge state (anionic, cationic, zwitterionic), and sequence composition to optimize both selectivity and safety. These parameter adjustments allow tuning of binding affinity and specificity to achieve high mutant allele targeting while reducing off-target hybridization.
2Reliability
If oligonucleotide length is increased to improve binding affinity, then hybridization stability is improved, but delivery efficiency deteriorates
Solution Approach 1:
The patent applies composite materials by combining different backbone chemistries (DNA, RNA, LNA, PNA) with various charge states and incorporating chemical modifications such as phosphorodiamidate morpholino oligomers (PMOs) and peptide nucleic acids (PNAs). These composite oligonucleotide structures provide enhanced stability and affinity while maintaining manageable sizes for delivery, effectively resolving the contradiction between hybridization stability and delivery efficiency.
3Ease of operation
If cationic modifications are added to improve cellular uptake, then cell penetration is improved, but cytotoxicity increases
Solution Approach 1:
The patent employs parameter changes by systematically adjusting the charge density and distribution of cationic modifications, using partial rather than complete cationic substitution, and optimizing the ratio of cationic to neutral linkages. This controlled approach enables sufficient cellular uptake enhancement while maintaining cytotoxicity at acceptable levels through precise parameter optimization.
Solution Approach 2:
The patent applies this principle by using transient cationic modifications that provide the necessary cellular uptake function temporarily during delivery, then are neutralized or removed once inside the cell. This allows the oligonucleotides to exploit cationic properties for entry without sustaining the cytotoxic effects associated with permanent cationic charges.
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 antisense oligonucleotides effectively selectively reduce the expression of mutant proteins relative to wild-type proteins, potentially slowing disease progression and improving treatment outcomes for expanded repeat diseases.
Implementation Method 1
antisense oligonucleotides that specifically hybridize to mutant mRNA produced from expanded nucleotide repeat alleles, using sequences complementary to the expanded repeats
Data Source
AI summary
The invention provides for a method for selectively reducing the expression of a mutant mRNA and/or protein having an expanded nucleotide repeat relative to a wild-type mRNA, comprising contacting a cell with an antisense oligonucleotide of sufficient length and complementarity to the expanded nucleotide repeat. More particularly it relates to selectively reducing the expression of mutant Huntington protein associated with Huntington's disease. The antisense oligonucleotide comprising either a nucleotide or a repeated three nucleotide sequence as defined in the claims.