Overview of Enzerna’s technology: Artificial Site-Specific RNA Endonucleases (ASREs) are rationally designed proteins consisting of an RNA endonuclease domain and RNA binding domains called PUF, that specifically recognize any 8-nucleotide RNA sequence. ASRE can be used to specifically cleave (and thus inactivate) any disease-causing RNA, and Combined with gene delivery vectors, ASREs provide a new strategy for selective degradation of pathogenic transcripts associated with triplet nucleotide disorders.
ASRE Technology: High Specific and Highly Differentiated
Targeting the pathogenic RNA or protein with ASRE-Technology offers an avenue for curative therapies. Antisense oligonucleotide (ASO) and RNA interference (RNAi)- based therapies have been shown to be effective in isolated cells. However, these therapies are limited by the need for lifelong administration, poor delivery across the blood brain barrier, and passive delivery to target cells in vivo. While antisense RNAs could be delivered via gene therapy, to date, targeting efficiency remains unacceptably low.
For many diseases, gene edited, most notable using CRISPR/Cas DNA editing technology offers an opportunity to correct mutant alleles. Unfortunately, given the mechanism of the gene editing process, CRISPR/Cas does not offer a viable therapeutic approach. Provided the editing machinery can be delivered to the appropriate cells, for each cell that undergoes a DNA editing event (intiated by a single double stranded break), one or more of several outcomes are possible:
(a) the mutant and/or normal allele will be targeted by the DNA editing enzyme where a random in frame deletion will occur to decrease the repeat length (desired event);
(b) the mutant and/or normal allele will be targeted by the DNA editing enzyme where a random in frame expansion will occur to increase the repeat length (adverse event);
(c) the mutant and/or normal allele will be targeted by the DNA editing enzyme where a random out of frame deletion or expansion will occur (adverse event);
(d) no change in mutant and/or normal allele. Since, each of the events will occur randomly (i.e., cannot be controlled) in each cell that is transduced with the editing machinery, CRISPR/Cas does not offer a viable therapeutic at this time.