There have been major advances in RNA-based therapeutics (siRNA, miRNA and antisense oligonucleotides) recently, so that it now offers great potential to treat a range of human disorders, including hypercholesterolaemia, cancer and neurodegenerative disease. Drugs developed with 2nd generation chemistry are proving very successful in clinical trials. For example, a recent report showed that 3-monthly sc injections of siRNA targeting PCSK9 very efficiently reduced LDL cholesterol in patients already on statins and were well tolerated (NEJM, 2017,376:1430). Key to this advancement has been (i) the enhanced stability afforded by structural modifications; (ii) liver-specific delivery and (iii) dispensing with a lipid carrier/vehicle, the latter a potential cause of dose- and therapy-limiting adverse effects.
The development of miRNAs as cancer therapeutics is illustrated by miR-34a, which was the first miRNA to enter clinical trials in the US to treat solid cancers, predominantly liver (HCC) and renal cancer. The approach used 1st generation chemistry and a lipid vehicle, and although there were some promising therapeutic effects, adverse effects from the lipid carrier prevented further development.
We have been developing a microRNA for therapy, miR-7, which is a potent inhibitor of the EGF-receptor (EGFR) signaling pathway in multiple human tumors, including HCC. miR-7 powerfully inhibits HCC growth in vitro and in vivo, and can overcome resistance to the only available tyrosine kinase inhibitor, sorafenib. In collaboration with a US-based RNA therapeutics company, we have designed 2nd generation chemistry modifications to miR-7 so that it does not require a lipid vehicle and can be targeted to the liver specifically.
The talk will provide an overview of the current state of RNA-based therapeutics, their developing role in the treatment of hypercholesterolaemia and their potential for cancer treatment, with emphasis on miR-7 as a therapy for HCC.