PHARMACOKINETIC CONSIDERATIONS IN SOMATIC GENE-THERAPY

It is anticipated that gene therapies will be useful for achieving lon g durations of action with little temporal fluctuation in the level of the therapeutic gene product, localized effects in specific tissues o r cell types, and levels of biological products that can be regulated over time by drugs or physiological events. The effective clinical app lication of gene therapies will require detailed consideration of the pharmacokinetics of the gene and its gene product. This requires under standing not only the apparent kinetics of the bioactive gene product, but the intrinsic kinetics of each step involved in gene delivery, ge ne expression and the bioavailability of the gene product. Numerical m odels are described for three different approaches to gene therapy: (i ) those that involve permanent integration of a transgene into the tar get cell, (ii) those that involve transient residence of the transgene within the cell, and (iii) those that allow control over gene express ion by regulatory factors or administered drugs. Experimental studies describing the dynamics and kinetics of DNA in vivo and early pharmaco kinetic studies of viral and non-viral systems are reviewed. (C) 1998 Elsevier Science B.V.