MULTICOMPARTMENT, NUMERICAL-MODEL OF CELLULAR EVENTS IN THE PHARMACOKINETICS OF GENE THERAPIES

DNA expression vectors may be administered to patients like convention al medicines to have a finite and controlled duration of action. The c linical application of these medicines will require a precise understa nding of the kinetics of the administered gene, the mRNA transcript, a nd the gene product. The apparent kinetic properties of the therapeuti c gene product, including the level and duration of action, will be de termined by various intrinsic kinetic processes including: (i) distrib ution 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-translationa l processing, distribution, and fate of the gene product. To consider in a theoretical manner how the intrinsic kinetics of cellular process es may affect the apparent level of a therapeutic gene product over ti me, 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 ove r time are calculated with different values for the intrinsic t(1/2) o f DNA in the MILIEU, ENDOSOME, and CELL; the intrinsic t(1/2) of mRNA; the intrinsic t(1/2) of the gene product; endosomal stability; and tr anscription 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 ea ch affect the level of the product and highlights strategies for enhan cing the therapeutic profile of gene therapies.