Antisense Oligonucleotide Delivery with Charged Polymer Balance
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Solution Overview
Problem
Conjugation of antisense oligonucleotides with positively charged polymers enhances delivery but increases toxicity, limiting their therapeutic window and effectiveness in treating genetic disorders and infections.
Innovation Solution
Combining antisense oligonucleotides with both positively charged and negatively charged or amphiphilic polymers to reduce cell toxicity while maintaining or enhancing delivery efficiency, using specific ratios and types of polymers like phosphorodiamidate morpholino oligomers and peptide nucleic acids with negatively charged oligonucleotides or amphiphilic polymers.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If antisense oligonucleotides are conjugated with positively charged polymers to enhance delivery effectiveness, then cell delivery efficiency is improved, but cell toxicity increases significantly
Solution Approach 1:
The patent introduces a negatively charged polymer as an intermediary component that complexes with the positively charged polymer-conjugated antisense oligonucleotide. This intermediary negatively charged polymer mediates the interaction between the cationic delivery vehicle and cellular components, reducing direct toxic effects while maintaining delivery efficiency. The complex formation allows the positive charges to function for delivery without the full toxic impact of the positively charged polymer alone.
Solution Approach 2:
The patent changes the charge parameter of the formulation by combining positively and negatively charged components. The net charge of the complex is modulated by varying the ratio of negatively charged polymer to positively charged polymer-conjugated oligonucleotide. This parameter change allows optimization of both delivery efficiency and toxicity profile, achieving effective delivery at reduced toxic doses.
2Productivity
If the dosage of antisense oligonucleotides is increased to overcome limited therapeutic window, then treatment effectiveness may improve, but toxicity approaches LD50 dosage levels
Solution Approach 1:
The negatively charged polymer acts as a protective intermediary that allows higher dosages of antisense oligonucleotide to be administered without reaching toxic LD50 levels. The complex formation distributes the oligonucleotide in a less toxic format, enabling effective therapeutic dosing while maintaining safety margins.
Solution Approach 2:
The patent creates a composite formulation combining antisense oligonucleotide, positively charged polymer, and negatively charged polymer. This composite material achieves enhanced therapeutic effectiveness through the synergistic combination of components, allowing effective dosing while the negative/positive charge balance mitigates toxicity concerns.
3Object-affected harmful factors
If negatively charged polymers are combined with positively charged polymer-conjugated antisense oligonucleotides, then cell toxicity is reduced, but there is concern that positive charge effects may be neutralized
Solution Approach 1:
The patent carefully controls the charge parameters by adjusting the ratio of negatively charged polymer to positively charged polymer-conjugated oligonucleotide. This parameter optimization ensures that enough positive charge remains to provide delivery enhancement while sufficient negative charge is present to reduce toxicity. The stoichiometric balance is critical for resolving this contradiction.
Solution Approach 2:
The negatively charged polymer serves as an intermediary that modulates rather than completely neutralizes the positive charge effects. The complex allows controlled interaction where positive charges facilitate delivery and negative charges mitigate toxicity, with the overall effect being a balance achieved through proper formulation ratios.
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 combination significantly reduces cell toxicity and improves the delivery and efficacy of antisense oligonucleotides, allowing for higher dosages and broader therapeutic applications, including viral infections, cancers, and muscular dystrophy, without neutralizing the enhancing effects of positive charges.
Implementation Method 1
combining the ON-PCP compounds with negatively charged polymers
Implementation Method 2
the enhanced delivery is due to the binding of the positively charged polymer to the cell membrane
Data Source
AI summary
The invention provides compositions and associated methods for the antisense treatment of genetic disorders, infections and various other medical conditions. In particular, embodiments of the present invention are directed to pharmaceutical compositions comprising a combination of an antisense oligonucleotide compound conjugated with a positively charged polymer (“ON-PCP”) and a negatively charged polymer. Pharmaceutical compositions in accordance with the present invention have demonstrated improved antisense efficiency and reductions in cell toxicity compared to compositions that contain an oligonucleotide compound conjugated with a positively charged polymer.