PTH1 Ligand-Bound Nucleic Acid Complex for Organ-Specific Delivery
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Solution Overview
Problem
Current nucleic acid medicine delivery methods, particularly those targeting the PTH1 receptor, face challenges in specifically delivering nucleic acid complexes to organs like the kidney and bone, leading to off-target effects and safety concerns due to non-specific binding to cells with LDL receptors.
Innovation Solution
A ligand-binding nucleic acid complex is developed, where a PTH1 ligand, specifically a peptide with a defined amino acid sequence, binds to a nucleic acid molecule, allowing for targeted delivery to PTH1 receptor-expressing organs through intravenous or subcutaneous administration, utilizing a linker for enhanced specificity and efficacy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If a ligand that binds to LDL receptors is used for delivery, then the nucleic acid complex can be delivered to the liver, but the nucleic acid complex is also delivered to other organs with LDL receptors, causing off-target effects
Solution Approach 1:
The patent applies local quality by switching from a general ligand (LDL receptor binder) to a specific ligand (PTH1 receptor binder) that targets only the desired organ. The PTH1 receptor is predominantly expressed in the kidney, providing localized delivery to the target organ while avoiding other organs with LDL receptors, thus eliminating off-target effects while maintaining reliable delivery to the intended target.
2Reliability
If a nucleic acid molecule with large molecular weight is bound to a ligand, then the complex can deliver the nucleic acid, but it becomes difficult to predict whether the complex would be integrated into a cell
Solution Approach 1:
The patent applies parameter changes by carefully controlling the molecular weight of the ligand component. The PTH1 ligand used is a relatively small peptide or protein, which keeps the overall complex size manageable. This parameter optimization ensures that the complex maintains delivery capability while remaining small enough to be efficiently taken up by cells through receptor-mediated endocytosis, making integration predictable and reliable.
3Ease of manufacture
If a single-stranded oligonucleotide is used, then the construct is simple to prepare, but single-molecule annealing requires physiological conditions to form the double-stranded structure
Solution Approach 1:
The patent applies preliminary action by pre-forming the double-stranded hetero-duplex structure during the oligonucleotide synthesis process itself. The antisense strand and sense strand are designed to anneal to each other, forming a stable double-stranded structure before administration. This preliminary formation of the active structure eliminates the need for separate annealing steps in physiological conditions and ensures the complex is ready for immediate therapeutic action.
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 ligand-binding nucleic acid complex effectively regulates the expression or editing of target genes in organs expressing the PTH1 receptor, providing a therapeutic option for diseases by ensuring organ-specific delivery and minimizing off-target effects.
Implementation Method 1
a ligand reacting with a receptor exposed on the target cell surface
Implementation Method 2
an antisense strand comprising a nucleic acid sequence capable of hybridizing to a target gene or target transcription product
Data Source
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AI summary
This invention provides a PTH1 ligand-binding nucleic acid complex that is delivered to a target organ to regulate expression or editing of a target gene or a transcription or translation product thereof. The PTH1 ligand-binding nucleic acid complex in which a nucleic acid comprising an antisense strand comprising an oligonucleotide having a nucleotide sequence complementary to a target transcription product and consisting of 12 to 30 nucleotides is bound to a PTH1 ligand is delivered to an organ to regulate expression or editing of a target gene or a transcription or translation product thereof. Thus, such nucleic acid complex is useful for treatment of a disease caused by such gene. In addition, the ligand-binding nucleic acid complex can be delivered to an organ, tissue, or cell in which the PTH1 receptor is expressed, such as the kidney, bone, and subcutaneous fat tissue, or the vascular endothelial cells. Thus, such nucleic acid complex is useful for treatment of diseases in such organs.