Modified Oligonucleotides for TMPRSS6 Modulation
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Solution Overview
Problem
Current therapeutic strategies for treating iron overload disorders are limited, and there is a need for highly potent and tolerable compounds to inhibit TMPRSS6, as existing nucleic acid inhibitors have not been approved for clinical use.
Innovation Solution
Development of modified oligonucleotides that target the TMPRSS6 sequence to modulate its expression levels, specifically comprising 12 to 30 linked nucleosides with a nucleobase sequence that is at least 80% complementary to the TMPRSS6 mRNA, to reduce iron accumulation in animals.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If nucleic acid inhibitors (siRNA, antisense oligonucleotides) are used to target TMPRSS6, then TMPRSS6 expression can be reduced, but the compounds have not been approved for clinical use due to insufficient potency or tolerability
Solution Approach 1:
The patent applies parameter changes by modifying the chemical structure of oligonucleotide compounds through various substitutions (e.g., 2'-O-methoxyethyl, constrained ethyl, LNA modifications) and internucleoside linkage changes (e.g., phosphorothioate, morpholino). These structural parameter modifications enhance both the potency and tolerability of the compounds, enabling clinical approval while maintaining effective TMPRSS6 inhibition.
2Productivity
If highly potent inhibitors are developed to achieve effective TMPRSS6 suppression, then therapeutic efficacy improves, but tolerability and safety may be compromised
Solution Approach 1:
The patent applies local quality by introducing specific chemical modifications at particular positions within the oligonucleotide structure. Different regions of the molecule are modified with different chemical groups (e.g., 2'-O-methoxyethyl at certain positions, phosphorothioate linkages at others) to optimize local interactions with biological targets while minimizing off-target effects, thereby achieving both high potency and good tolerability.
Solution Approach 2:
The patent applies composite materials by creating chimeric oligonucleotide structures that combine multiple types of nucleosides and linkages within a single molecule. These composite structures integrate different chemical properties (e.g., modified sugars, base modifications, alternative linkages) to achieve a balance between potent TMPRSS6 inhibition and reduced immunogenicity or toxicity, improving overall tolerability.
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 effectively lower TMPRSS6 levels, thereby reducing iron overload and associated complications by modulating the expression of TMPRSS6, providing a potential therapeutic approach for iron-related disorders.
Implementation Method 1
a modified oligonucleotide consisting of 12 to 30 linked nucleosides and having a nucleobase sequence comprising a portion of at least 8 contiguous nucleobases complementary to an equal length portion of nucleobases 3162 to 3184 of SEQ ID NO: 1
Data Source
AI summary
Disclosed herein are compositions and compounds comprising modified oligonucleotides for modulating TMPRSS6 and modulating an iron accumulation disease, disorder and/or condition in an individual in need thereof. Iron accumulation diseases in an individual such as polycythemia, hemochromatosis or β-thalassemia can be treated, ameliorated, delayed or prevented with the administration of antisense compounds targeted to TMPRSS6.