mRNA therapeutic applications are growing, however at the clinical stage, they are facing a similar failure rate as of small molecules !
To overcome the challenges of mRNA development, pre-clinical assessments in Zebrafish Models can ensure clinical safety and efficacy through the below assessments.
Target modulation:
For mRNA target modulation measure, gene expression profile of zebrafish research models at pre and post mRNA delivery can be assessed.
Pre mRNA Targets:
Models can be validated for the presence of similar splicing variants as in humans and pre mRNA targets can be modulated in models.
Minimizing Immunogenicity:
In most cases the mRNA in itself is not immunogenic, however the coding protein could be immunogenic at reactive concentrations. Construct optimization to eliminate immunogenicity can be assessed in models.
In Vivo delivery:
Target protein threshold achievement could be challenged by mRNA effectors. These effectors could be tissue specific or pathology specific. Target protein threshold could be quantified by ELISA readouts in models.
Kinetics:
Availability of Target protein at a specific tissue site is vital to success of mRNA therapy. In cases where the target protein needs to be within a specific organ, if there is a lack of mRNA accessibility into the organ and lack of transporters for the protein into that organ, this may lead to low kinetics leading to lack of efficacy. Kinetic assessments can be made by tissue specific target protein assessment.
Duration of action:
A continual expression of mRNA for availability of target protein to ensure successful proteome shift is needed. Such shifts are not possible without reaching threshold limits. Time duration quantification of target protein can be done in the model.
Are effects chronic or repressed?
mRNA therapeutic response can be acute or chronic. To ensure response is chronic, repression of expression can be validated in the model.
Precision Oncology:
In the case of certain target proteins, tissue concentrations play an important role. One may want a relative expression ratio for therapeutic potential. Such is the case in several oncology targets and these target protein ratios can be assessed in the model.
mRNA loading assessment:
In the case of encapsulated mRNA delivery, pay load assessments and shuttle instruction outcomes can be assessed in zebrafish models.
Reach out to Viji@pentagrit.com for research queries.