LNP Protein Expression via IV Tolerance Induction
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Solution Overview
Problem
Current lipid nanoparticles (LNPs) used for in vivo delivery of active agents, such as nucleic acids, induce an innate immune response upon non-intravenous administration, leading to reduced protein expression and therapeutic efficacy due to immune recognition and activation, which limits repeated dosing and causes adverse effects.
Innovation Solution
Modifying the structural aspects of LNPs and their cargo to dampen immune responses, specifically through the use of microRNA binding sites and chemical modifications, and employing an initial intravenous administration to induce tolerance for subsequent non-intravenous administrations, thereby reducing immune cell activation and maintaining protein expression.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If traditional LNPs are administered non-intravenously, then protein delivery is achieved, but immune response is induced leading to reduced protein expression
Solution Approach 1:
An initial intravenous administration of LNP is performed before non-intravenous administrations to induce immune tolerance. This preliminary action conditions the immune system to accept subsequent non-intravenous doses without triggering harmful immune responses, thereby maintaining reliable protein expression across multiple dosing events.
Solution Approach 2:
The administration route parameter is changed from exclusively intravenous to a sequence involving initial intravenous followed by non-intravenous (subcutaneous, intramuscular, or intradermal) administrations. This parameter change optimizes both immune tolerance induction and practical deliverability while maintaining protein expression reliability.
2Duration of action of stationary object
If repeated dosing of LNPs is performed, then therapeutic effect is maintained, but immune response increases causing loss of protein expression
Solution Approach 1:
The first intravenous LNP administration serves as a preliminary tolerizing event that enables subsequent repeated non-intravenous dosing. This preliminary action establishes immune tolerance that persists through multiple therapeutic dosing events, preventing the progressive loss of protein expression that would otherwise occur with repeated administrations.
Solution Approach 2:
The dosing regimen employs periodic administrations where the first dose is intravenous and subsequent doses are non-intravenous. This periodic pattern with alternating administration routes maintains therapeutic effect over time while preventing immune-mediated loss of protein expression through the tolerizing effect of the initial IV dose.
3Ease of operation
If LNPs are administered non-intravenously, then delivery frequency is improved, but adverse effects increase due to immune activation
Solution Approach 1:
The initial intravenous LNP administration acts as a preliminary step that induces immune tolerance, thereby enabling subsequent non-intravenous administrations to proceed without harmful immune activation. This preliminary tolerizing event removes the barrier to frequent non-intravenous dosing while preventing adverse effects.
Solution Approach 2:
The initial intravenous LNP dose serves as an intermediary event that mediates between the desire for frequent non-intravenous dosing and the need to avoid immune-mediated adverse effects. This intermediary administration establishes the immunological conditions that permit safe and frequent subsequent dosing.
Data Source
AI summary
This disclosure provides improved lipid-based compositions, including lipid nanoparticle compositions, and methods of use thereof for delivering nucleic acids in vivo. These compositions have reduced immune activation resulting in accelerated blood clearance and/or anti-drug antibodies and they have an improved toxicity profile and therapeutic index in vivo.