Oral Presentation The Joint Annual Scientific Meetings of the Endocrine Society of Australia and the Society for Reproductive Biology 2017

RNA-based therapeutics: the new kid on the block. (#55)

Peter J Leedman 1 2
  1. School of Medicine and Pharmacology, University of Western Australia, Perth, WA, Australia
  2. Laboratory for Cancer Medicine, Harry Perkins Institute of Medical Research, Nedlands, Western Australia, Australia

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.