Technology
DNAzymes

DNAzymes, like sterna`s hgd40, are catalytically active DNA molecules.

The ones of the so-called 10-23 family are specifically characterized by their capability to bind to and cleave mRNA molecules. 10-23 DNAzymes consist of two binding domains flanking a central catalytic domain. The latter is composed of 15 deoxynucleotides, the sequence of which is conserved throughout all molecules within this specific DNAzyme class. In contrast, the binding domains are variable and are designed to specifically bind the mRNA of interest.

After binding of a DNAzyme via its binding domains to the corresponding sequence in the target mRNA,

Image

…the catalytic domain becomes activated and directly cleaves the target mRNA molecule.

Image

After successful cleavage of a target mRNA molecule, the DNAzyme-RNA-complex dissociates and the RNA cleavage products are further degraded by endogenous, intracellular enzymes. The DNAzyme molecule is then available for subsequent binding and cleavage of additional mRNA molecules.

Image

The consequence of mRNA degradation is that translation into protein is incapacitated and the reduction in functional protein then results in an inhibition of all down-stream events. The enzymatic activity of DNAzymes is Mg2+-dependent, however, no additional endogenous co-molecules are required for the activation of these molecules. Thus, DNAzymes represent a particular class of antisense molecules combining the superior specificity of antisense molecules with inherent catalytic activity. This makes them ideal for the specific interference with disease-relevant molecules and processes.

In summary, key characteristics and major advantages of DNAzymes include high target specificity, gymnotic delivery (no chemical modification and/or transfection reagents required for intracellular delivery), direct mRNA degradation, continuous enzymatic activity (one DNAzyme can cleave many mRNAs), fully synthetic manufacturing (highly economical production process), local administration (no systemic side effects), and a solid safety/efficacy profile.

Image
Image

After successful cleavage of a target mRNA molecule, the DNAzyme-RNA-complex dissociates and the RNA cleavage products are further degraded by endogenous, intracellular enzymes. The DNAzyme molecule is then available for subsequent binding and cleavage of additional mRNA molecules (step 3).

Image

The consequence of mRNA degradation is that translation into protein is incapacitated and the reduction in functional protein then results in inhibition of all down-stream events e.g. cytokine expression. Enzymatic activity of DNAzymes is Mg2+-dependent, however, no additional endogenous co-molecules are required for the activation these molecules. Consequently, the activity of a DNAzyme is independent of the endogenous molecular machinery its cells. Therefore, DNAzymes represent a particular class of antisense molecules combining superior target specificity with inherent catalytic activity. This makes them an attractive pharmacological tool for highly specific interference with disease-causing molecules and mechanisms.