Targeting Cancer-Associated Transcripts with Engineered RNase P Ribozymes

Nucleic acid-based gene interfering and editing molecules, such as antisense oligonucleotides, ribozymes, small interfering RNAs (siRNAs), and CRISPR-Cas9-associated guide RNAs, are promising gene-targeting agents for therapeutic applications. Cancer’s heterogeneous and diverse nature demands gene-silencing technologies that are both specific and adaptable. RNase P ribozymes, called M1GS RNAs, are engineered constructs that link the catalytic M1 RNA from bacterial RNase P to a programmable guide sequence. This guide sequence directs the M1GS ribozyme to base-pair with a target RNA, inducing it to fold into a structure resembling pre-tRNA. Catalytic activity can be enhanced through in vitro selection strategies. In this review, we will discuss the application of M1GS ribozymes in targeting cancer-associated RNAs, focusing on the BCR-ABL transcript in leukemia, the internal ribosome entry site (IRES) of hepatitis C virus (HCV), and the replication and transcription activator (RTA) of Kaposi’s sarcoma-associated herpesvirus (KSHV). Together, these examples highlight the versatility of M1GS ribozymes across both viral and cellular oncogenic targets, underscoring their potential as a flexible synthetic biology platform for cancer therapy.