RALDH modRNA Vaccines for Mucosal Homing Without ATRA Toxicity
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current vaccines often fail to induce effective mucosal immune responses, particularly at gastrointestinal, respiratory, and genital mucosal surfaces, due to poor antigen stability and tolerogenic responses in the gastrointestinal tract, and challenges in generating tissue resident memory cells at uterine or vaginal mucosa.
Innovation Solution
Development of modified polynucleotides, such as mRNA encoding retinaldehyde dehydrogenase (RALDH), which upregulate mucosal homing receptors on activated lymphocytes, allowing targeted antigen-specific responses and mucosal tissue targeting, avoiding toxic effects of all-trans retinoic acid.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If oral vaccines are used to target intestinal mucosa, then mucosal immune response is induced, but antigen stability deteriorates and tolerogenic response occurs
Solution Approach 1:
The patent uses modified RNA (modRNA) encoding retinaldehyde dehydrogenase (RALDH) as an intermediary molecule that is administered parenterally. This modRNA acts as a mediator to induce RALDH protein expression in dendritic cells, which then produce retinoic acid to drive mucosal homing receptor upregulation on lymphocytes, achieving mucosal immune response without direct oral exposure to unstable antigens
Solution Approach 2:
The patent replaces the mechanical/oral administration system with a parenteral administration system delivering modRNA. This substitution avoids the harsh gastrointestinal environment that degrades antigens, while still achieving mucosal tissue targeting through the molecular mechanism of RALDH-induced retinoic acid production and subsequent lymphocyte homing
2Ease of operation
If all-trans retinoic acid (ATRA) is used to induce mucosal homing, then mucosal tissue targeting is achieved, but toxicity occurs
Solution Approach 1:
The patent uses modRNA encoding RALDH as an intermediary that indirectly produces ATRA within dendritic cells. This indirect production mechanism allows ATRA to be generated locally and transiently for mucosal homing induction, while avoiding the systemic toxicity associated with direct ATRA administration. The modRNA serves as a controlled delivery vehicle that limits ATRA production to specific cells and time windows
Solution Approach 2:
The patent changes the temporal and spatial parameters of ATRA production by using modRNA to induce RALDH expression only in dendritic cells for limited durations. This parameter control ensures ATRA is produced at appropriate concentrations and for appropriate times to induce mucosal homing, while avoiding chronic or systemic ATRA exposure that causes toxicity
3Reliability
If parenteral vaccines are used to avoid tolerogenic effects, then immune response is improved, but mucosal tissue targeting becomes difficult
Solution Approach 1:
The patent introduces modRNA encoding RALDH as a molecular intermediary that bridges parenteral administration with mucosal tissue targeting. When administered parenterally, this modRNA is taken up by dendritic cells, which then produce retinoic acid to upregulate mucosal homing receptors on activated lymphocytes, enabling these lymphocytes to home to mucosal tissues. This intermediary mechanism allows parenteral administration to achieve mucosal targeting that would otherwise be difficult to accomplish
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 polynucleotides enable robust parenteral vaccine formulations that effectively target mucosal tissues, inducing antigen-specific immunity without tolerogenic effects, and can be used in cancer immunotherapy and to treat mucosal infections and cancers.
Implementation Method 1
RALDH was selected due to its ability to indirectly upregulate mucosal homing receptors on activated lymphocytes
Data Source
AI summary
Some aspects of this disclosure provide modified mRNA (modRNA) encoding retinaldehyde dehydrogenase (RALDH) enzyme, in addition to methods of synthesis, administration, use, and treatment. In some embodiments, the modRNA may be used in a vaccine to treat infections (e.g., mucosal infections) and/or cancers (e.g., mucosal cancers).