TMPRSS6-Silencing Nucleic Acids With Iron Chelation for Iron Overload
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Solution Overview
Problem
Current methods for treating disorders associated with iron overload, such as hemochromatosis and β-thalassemia, are limited by the complexity of identifying potent nucleic acid silencing triggers with minimal off-target effects, and there is a need for effective treatments to reduce systemic iron levels to prevent infections and non-relapse related mortality in bone marrow transplantation.
Innovation Solution
A nucleic acid that inhibits TMPRSS6 gene expression, combined with iron chelators, is administered to target tissues, enter cells, and function within acceptable toxicity limits, using specific sequences and modifications to enhance efficacy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Device complexity
If algorithms are used to design nucleic acid silencing triggers, then the design process is simplified, but the potency and specificity of the triggers are reduced due to inability to account for tertiary structure and RNA binding proteins
Solution Approach 1:
The patent uses experimental methods as an intermediary between algorithmic design and final trigger selection. High-throughput screening experiments serve as a mediator to evaluate the actual performance of algorithmically designed triggers, accounting for complex factors like tertiary structure and RNA binding proteins that algorithms cannot predict. This intermediary step bridges the gap between simplified computational design and reliable functional performance.
2Reliability
If extensive experimental methods are used to identify potent siRNAs, then trigger potency is improved, but the discovery process becomes complex and time-consuming
Solution Approach 1:
The patent performs preliminary computational screening and filtering of potential siRNA sequences before experimental validation. Algorithms are used to pre-select candidates based on basic design criteria, reducing the number of sequences that require extensive experimental testing. This preliminary action reduces the overall complexity and time of the discovery process while maintaining the ability to identify potent triggers through subsequent experimental evaluation.
3Reliability
If nucleic acid silencing triggers are developed for therapeutic use, then treatment efficacy is improved, but issues of synthesis cost, distribution, cellular entry, and toxicity arise
Solution Approach 1:
The patent employs chemical modifications of the nucleic acid triggers to improve their pharmacological properties. Modifications to the sugar-phosphate backbone, base structures, or terminal groups alter parameters such as nuclease resistance, cellular uptake efficiency, and toxicity profile. These parameter changes enable the triggers to maintain treatment efficacy while improving manufacturability, stability for distribution, and safety for therapeutic use.
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 nucleic acid effectively reduces TMPRSS6 expression, lowering iron levels and reducing the risk of infections and mortality in patients with iron overload and bone marrow transplantation.
Implementation Method 1
Double-stranded RNA (dsRNA) able to complementarily bind expressed mRNA has been shown to be able to block gene expression by a mechanism that has been termed RNA interference (RNAi). RNAi is mediated by the RNA-induced silencing complex (RISC), a sequence-specific, multi-component nuclease that destroys messenger RNAs homologous to the silencing trigger loaded into the RISC complex.
Implementation Method 2
Short dsRNAs direct gene-specific, post-transcriptional silencing in many organisms, including vertebrates. The nucleic acid comprises a duplex region that comprises a first strand and a second strand that is at least partially complementary to the first strand, wherein said first strand is at least partially complementary to a portion of RNA transcribed from the TMPRSS6 gene.
Data Source
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AI summary
The present invention relates to products and compositions and their uses. In particular the invention relates to nucleic acid products that interfere with the TMPRSS6 gene expression or inhibits its expression in combination with one or more iron chelators and possibly other active agents, as well as therapeutic uses such as for the treatment of hemochromatosis, porphyria and blood disorders such as beta-thalassemia, sickle cell disease and transfusional iron overload or myelodysplastic syndrome, and infections and non-relapse related mortality associated with bone marrow transplantation.