Ribozyme Pharmacokinetic Screening for Predicting Pharmacodynamics Dosing Regimens

Author(s): Bekir Karlik

There have been only four studies published to datethat have addressed locally administered synthetic ribozyme pharmacodynamics in animals. A 2’-O-allyl modified ribozyme targeting amelogenin mRNA inhibited normal enamel formation after submandibular injection in neonatal mice. When injected intraarticularly in the knee, a stabilized ribozyme targeting stromelys in message reduced IL-1-stimulated stromelysin mRNA in rabbit synovium . An anti-protein kinase Cα mRNA targeting ribozyme, comprised totally of 2’-amino-modified ribonucleotide analogs, reduced subcutaneously implanted glioma tumor growth in rats. Finally, an in vitro transcribed ribozyme targeting TNF-α mRNA complexes with cationic lipids injected within the peritoneum decreased lipopolysaccharide-induced TNF-α expression in peritoneal cells obtained by lavage . Although this ribozyme was not chemically modified, use of a cationic lipid formulation likely enhanced the circulation time compared with unformulated ribozyme. Unfortunately, no studies have yet been published which explore the treatment of disseminated disease with systemically delivered synthetic ribozymes.