Multicompartment, numerical model of cellular events in the pharmacokinetics of gene therapies.
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 t1/2 of mRNA; the intrinsic t1/2 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.
Ledley
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Department of Space Physics and Astronomy, Rice University, Houston, TX 77251.
Ledley
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D002451:Cell Compartmentation / Q000235:genetics*; D004247:DNA / Q000493:pharmacokinetics*; D011992:Endosomes / Q000378:metabolism; D015316:Genetic Therapy; D005822:Genetic Vectors; D006207:Half-Life; D006801:Humans; D015233:Models, Statistical; D011401:Promoter Regions, Genetic; D014176:Protein Biosynthesis; D011506:Proteins / Q000493:pharmacokinetics; D012333:RNA, Messenger / Q000493:pharmacokinetics; D012680:Sensitivity and Specificity; D014158:Transcription, Genetic
D011506:Proteins; D012333:RNA, Messenger; D004247:DNA