Gene Therapy: A Pharmacokinetic/Pharmacodynamic Modelling Overview

Abstract

Since gene therapy started over 20 years ago, more than one-thousand clinical trials have been carried out. Nonviral vectors present interesting properties for their clinical application, but their efficiency in vivo is relatively low, and further improvements in these vectors are needed. Elucidating how nonviral vectors behave at the intracellular level is enlightening for vector improvement and optimization. Model-based approach is a powerful tool to understand and describe the different processes that gene transfer systems should overcome inside the body. Model-based approach allows for proposing and predicting the effect of parameter changes on the overall gene therapy response, as well as the known application of the pharmacokinetic/pharmacodynamic modelling in conventional therapies. The objective of this paper is to critically review the works in which the time-course of naked or formulated DNA have been quantitatively studied or modelled.

Comparative cellular pharmacokinetics and pharmacodynamics of siRNA delivery by SPANosomes and by cationic liposomes

“…29 Consequently, a global understanding of the pharmacokinetic/pharmacodynamic of siRNA NCs is of critical importance. 9 …”

“…6,7 Consequently, there is a pressing need to elucidate the relationship between the cellular pharmacokinetics and the biological activity of NC- delivered siRNA. 8,9 Moreover, the cellular pharmacokinetic studies can aid in identification of cellular barriers and the rate-limiting steps for siRNA delivery, thus guiding design of nonviral vectors in the future.…”

Quantitative Aspects of Intracellularly-Targeted Drug Delivery

“…Mechanisms of intracellular gene delivery were studied more extensively and were quantified more thoroughly, as compared to small-molecule pharmacological agents, apparently due to somewhat easier quantification of DNA molecules. Subsequently, several mathematical models have been suggested to describe the mechanisms of DNA intracellular traffic and efficiency of nuclear delivery and of the resulting gene expression (23,24).…”

Kinetic and Dynamic Computational Model-Based Characterization of New Proteins in Mice: Application to Interferon Alpha Linked to Apolipoprotein A-I

“…A few examples where a modelling approach has been followed to evaluate the kinetic of different non-viral or viral vectors in order to improve their in vivo behaviour [25], [26], or to study the dynamic (efficiency) of vectors [27], [28], can be found in the literature. However and despite its advantages, its use in the gene therapy field is still limited [29], especially due to the amount of experimental data and computational resources needed, and our knowledge non-integrated kinetic/dynamic model has been develop so far in preclinical settings.…”