Multicompartment, Numerical Model of Cellular Events in the Pharmacokinetics of Gene Therapies

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Abstract
DNA expression vectors may be administered to patients like conventional medicines to have a finite and controlled duration of action. The clinical application of these medicines will require a precise understanding of the kinetics of the administered gene, the mRNA transcript, and the gene product. The apparent kinetic properties of the therapeutic gene product, including the level and duration of action, will be determined by various intrinsic kinetic processes including: (i) distribution and biological fate of the DNA expression vector; (ii) rates of DNA uptake into cells and dynamics of intracellular trafficking; (iii) half-life of the DNA vector in the cell; (iv) transcription rate; (v) half-life of mRNA; (vi) translation rate; and (vii) post-translational processing, distribution, and fate of the gene product. To consider in a theoretical manner how the intrinsic kinetics of cellular processes may affect the apparent level of a therapeutic gene product over time, we have constructed a multicompartment, numerical model. The model has six compartments, designated MILIEU, ENDOSOME, CELL, RNA, PROTEIN, and PRODUCT. The apparent level and kinetics of the gene product over time are calculated with different values for the intrinsic t1/2 of DNA in the MILIEU, ENDOSOME, and CELL; the intrinsic tl/2 of mRNA; the intrinsic tl/2 of the gene product; endosomal stability; and transcription rate. The model demonstrates how first-order kinetics can result from the summation of complex kinetic processes and provides a theoretical basis for future pharmacokinetic studies. This theoretical model illustrates how the half-lives of DNA, RNA, and gene product each affect the level of the product and highlights strategies for enhancing the therapeutic profile of gene therapies. Gene therapy with DNA expression vectors raises novel pharmacokinetic issues. The level of the gene product will be dependent upon the fate of the administered DNA vector, the kinetics of cellular processes including transcription, translation, and post-translational processing, and the fate of the gene product itself. These kinetic processes were studied using a multicompartment, numerical computer model. The model illustrates how the apparent level, duration of action, and half-life of the gene product can be determined by the intrinsic kinetics of the various steps in the delivery, uptake, and expression of the DNA vector. This study provides a theoretical foundation for developing products with an optimal therapeutic profile.