(M1530-02-08) PK/PD Modeling for Liver Targeting LNP Formulated tRNA in Transgenic Mice Containing a Premature Termination Codon on the Human Methylmalonyl-CoA Mutase (hMMut)

Purpose: The inherited rare disease methylmalonic acidemia (MMA) is caused by mutations in the human methylmalonyl-CoA mutase gene (hMMUT). A common mutation associated with MMA is a C→T single base mutation that produces a premature termination codon (PTC) – TGA. The purpose of this study is to develop a PK/PD Model for liver targeting LNP formulated tRNA in transgenic mice containing a premature termination codon on hMMut.

Methods: tRNA 1 is a synthetic Arg-TGA tRNA oligonucleotide carrying the anticodon recognizing the PTC. It is aminoacylated with Arginine in vivo and is subsequently able to insert the amino acid at the location of the nonsense mutation during translation, resulting in protein rescue of hMMUT. In vivo studies measured the liver distribution and pharmacokinetics (PK) of tRNA 1 delivered in lipid nanoparticles (LNP) in wild-type mice, and the pharmacodynamics (PD) of hMMUT protein rescue in transgenic mice carrying the human PTC mutation. A population PK/PD model was designed and applied to fit the observed PK and PD datasets.

Results: A semi-mechanistic tissue distribution PK model is developed and adequately fit to the observed time profiles of the tRNA and its natural modifications in WT mice. The PK model can sufficiently project the liver concentrations of the tRNAs (total and naturally modified) in the hMMut transgenic mice, enabling integration with PD effect. The integrated PK/PD model fits adequately to the time profiles of hMMut protein rescue observed in transgenic mice and is capable of projection for the PD effect in repeat doses, providing validation to the model.

Conclusion: An integrated population PK/PD model was developed to enable in-depth understanding of quantitative PK/PD relationships of hMMUT protein rescue in transgenic mice carrying the human PTC mutation. and provided a foundation for projection of efficacious dose and dosing regimen in humans.

integrated PK/PD model for tRNA Liver Distribution and hMMUT rescue


PopPK model fitting to observed concentrations in WT mice

Integrated PopPK/PD model fitting to observed protein rescue responses in hMMUT Tg mice