Modified Antisense Oligonucleotides for Palindromic Target Sequences
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Antisense oligomer compounds targeting sequences with biological palindromes or strings of three or more identical contiguous nucleobases face reduced activity and manufacturing challenges.
Innovation Solution
Modified antisense oligonucleotides with internal deletions of nucleobases to target sequences, including those associated with Duchenne muscular dystrophy, spinal muscular atrophy, and glycogen storage disease type II, enhancing activity and manufacturability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If antisense oligomer compounds are designed to target sequences with biological palindromes or strings of three or more identical contiguous nucleobases, then the compound can achieve specific targeting, but the antisense activity is compromised and manufacturing difficulties arise
Solution Approach 1:
The patent removes the problematic central nucleotide from the targeting sequence, extracting the source of the palindrome or repeated sequence. This creates a non-palindromic sequence that avoids the formation of stable secondary structures and prevents compromised antisense activity, while still maintaining specific targeting capability.
Solution Approach 2:
The patent introduces asymmetry into the targeting sequence by deleting the central nucleotide of a palindromic sequence or breaking a repeated sequence pattern. This asymmetric modification prevents the formation of symmetric secondary structures (such as hairpins or G-quadruplexes) that would otherwise reduce antisense activity, while preserving the ability to bind to the target RNA.
2Measurement precision
If antisense oligomer compounds target sequences with biological palindromes or strings of three or more identical contiguous nucleobases, then specific targeting is achieved, but manufacturing process difficulties occur
Solution Approach 1:
The patent extracts the central nucleotide from palindromic or repeated sequences in the targeting region. This modification simplifies the synthesis process by eliminating sequences that are difficult to manufacture due to their palindromic nature, which can cause aggregation and other manufacturing complications, while preserving the specificity of the oligomer for its target sequence.
3Measurement precision
If the targeting sequence includes a string of three or more identical contiguous nucleobases, then the oligomer can bind to specific target regions, but aggregation occurs during manufacturing
Solution Approach 1:
The patent removes the central nucleotide from strings of three or more identical contiguous nucleobases, extracting the source of aggregation. This creates a sequence that prevents the formation of stable aggregates during manufacturing and in vivo, while still allowing the oligomer to bind specifically to the target RNA through the remaining complementary bases.
Solution Approach 2:
The patent introduces asymmetry by deleting the central nucleotide of repeated sequences, breaking the symmetry that enables aggregate formation. This asymmetric modification prevents the oligomer from self-assembling into aggregates during manufacturing and in cellular environments, while preserving binding specificity through the non-palindromic sequence design.
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 modified oligonucleotides demonstrate improved antisense activity and reduced manufacturing issues, effectively targeting specific exon sequences for therapeutic applications.
Implementation Method 1
The subject oligonucleotide comprises a targeting sequence having a region complementary to at least one string of three or more identical contiguous nucleobases in a target sequence
Data Source
AI summary
A modified antisense oligonucleotide of about 10 to about 40 nucleobases is disclosed. The oligonucleotide comprises a targeting sequence having a region complementary to at least one string of three or more identical contiguous nucleobases in a target sequence, wherein the target sequence comprises at least one additional nucleobase compared to the region of the targeting sequence and the at least one additional nucleobase has no complementary nucleobase in the region of the targeting sequence, and wherein the targeting region complementary to the at least one string of three or more identical contiguous nucleobases is internal to the targeting sequence.