Plasmid delivery to muscle: Recent advances in polymer delivery systems.
Preclinical studies involving intramuscular injection of plasmid into animals have revealed at least four significant variables that effect levels of gene expression (i.e., >fivefold effect over controls), including the formulation, injection technique, species and pretreatment of the muscle with myotoxic agents to induce muscle damage. The uptake of plasmid formulated in saline has been shown to be a saturable process, most likely via a receptor-mediated event involving the T tubules and caveolae. Pharmacokinetic studies have demonstrated that the bioavailability of injected plasmid to muscle cells is very low, due to rapid and extensive plasmid degradation by extracellular nucleases. We have developed protective, interactive, non-condensing (PINC) delivery systems designed to complex plasmids and to (i) protect plasmids from rapid nuclease degradation, (ii) disperse and retain intact plasmid in the muscle and (iii) facilitate the uptake of plasmid by muscle cells. PINC systems result in up to at least a one log increase in both the extent and levels of gene expression over plasmid formulated in saline. We have combined the PINC delivery systems with two different muscle-specific expression plasmids. After direct intramuscular injection of these gene medicines, we have shown both local myotrophic and neurotrophic effects of expressed human insulin-like growth factor (hIGF-I) and the secretion of biologically active human growth hormone (hGH) into the systemic circulation.
Rolland
AP
GeneMedicine, Inc., 8301 New Trails Drive, The Woodlands, TX 77381-4248, USA
Mumper
RJ