The Therapeutic Potential of Ribozymes

Abstract

Ribozymes are catalytic RNA molecules that recognize their target RNA in a highly sequence-specific manner. They can therefore be used to inhibit deleterious gene expression (by cleavage of the target mRNA) or even repair mutant cellular RNAs. Targets such as the mRNAs of oncogenes (resulting from base mutations or chromosome translocations, eg, ras or bcr-abl) and viral genomes and transcripts (human immunodeficiency virus–type 1 [HIV-1]) are ideal targets for such sequence-specific agents. The aim of this review is therefore to introduce the different classes of ribozymes, highlighting some of the chemistry of the reactions they catalyze, to address the specific inhibition of genes by ribozymes, the problems yet to be resolved, and how new developments in the field give hope to the future for ribozymes in the therapeutic field.

Ribozyme-mediated REV1 inhibition reduces the frequency of UV-induced mutations in the human HPRT gene

“…Ribozymes are short RNA molecules that hybridize to a complementary target sequence of RNA and cleave this sequence catalytically and site-speci®cally in the absence of proteins (14). The`hammerhead' ribozyme element is usually only 30±40 bases long, and is composed of two target recognition arms and a correctly folded catalytic domain (15). The advantages of employing such structurally simple RNA enzymes for in vivo settings are the ease of preparation, their speci®city and their negligible toxicity and immunogenicity.…”

Complete RNA inverse folding: computational design of functional hammerhead ribozymes

“…The nonexistence, as determined by , of any sequence folding into target structure S , which has GUG at the cleavage site and satisfies certain additional minimal constraints, strongly suggests that GUG is not a hammerhead cleavage site is due to the inability of the molecule to fold into a structure necessary for nucleophilic attack. Image of right panel adapted from figure 3A from ( 72 ), and both images produced by R2R ( 75 ).…”

A Discovery with Potential to Revitalize Hammerhead Ribozyme Therapeutics for Treatment of Inherited Retinal Degenerations

“…Trans-acting ribozymes are capable of intermolecular cleavage of many target molecules in vitro. However, in vivo trans-acting ribozymes have demonstrated only single-turnover target cleavage and require that the enzyme concentration be in substantial molar excess over the target RNA (James and Gibson 1998). 2+ and monovalent ions provide structural stability for tertiary interactions that position the core nucleotides to better facilitate the acid-base chemistry of cleavage (Martick and Scott 2006).…”