By: Prasad Subramaniam
The role RNA plays in normal health and disease progression has been investigated for more than two decades, showing dramatic advances with RNA becoming an increasingly important target for therapeutic intervention over the past ten years. Ever since the inception of the RNA Interference (RNAi) in 1998, methodology using antisense oligonucleotides which downregulate gene expression by either enzyme-dependent degradation of targeted mRNA or by blocking access of cellular machinery to pre-mRNA and mRNA without degrading the RNA (Kole 2012) have been of specific interest.
Scientists and pharmaceutical companies have concentrated much of their efforts to develop siRNA-based therapeutics to treat cancer and other genetic disorder diseases. With all these investments, siRNA-based therapeutics haven’t met success in clinical trials (OPKO Health shut down its phase 3 trial of an RNAi treatment for wet macular degeneration in 2009 after the intervention failed to meet the trial goals). Thus, several pharmaceutical companies have either shelved their siRNA programs or totally shut them down. For example, in 2010, Roche, which invested about $500 million in RNAi, shut down its internal research program. The following year, Pfizer and Abbott also pulled out of in-house RNAi development, and Merck shuttered the RNAi laboratory it had acquired in 2006 with its $1.1 billion purchase of Sirna Therapeutics.
Despite challenges, there has been a renewed interest in targeting RNA due to the emergence of a special class of compounds called morpholino oligonucleotides, which act as steric blockers at the RNA-splice sites and affect the way RNA is processed. The inclusion or exclusion of a single exon can have drastic effects, as seen in the cases of Duchenne Muscular Dystrophy (DMD), which is a severe form of muscular dystrophy caused by a genetic defect, or Spinal Muscular Atrophy (SMA), which is a debilitating motor nerve disease and is the second leading cause of hereditary neuromuscular disease after Duchenne muscular dystrophy. With these new chemical identities, which in essence work through a totally different mechanism than the RNAi, it is now possible to treat debilitating diseases like DMD and SMA. In fact, Sarepta Therapeutics has been granted a recent accelerated approval for their exon splicing compound ExonDys 51 (Eteplirsen) to treat DMD. A similar drug, Spinraza (Nusinersen), marketed by Biogen, has also been recently approved by the FDA to treat SMA, thus making these two drugs the first ever FDA-approved drugs for treating these neuromuscular disorders.
The strategy of utilizing RNA-splicing as a therapeutic approach can easily be applied to treat cancer as well. Unlike the siRNA-based therapeutics, morpholino-based antisense oligonucleotides are very stable in vivo and can be targeted to any splice site on any mRNA for blocking sites on RNA to obstruct RNA processing. Thus essentially, modulation of RNA-splicing could be used to destabilize oncogenic proteins by the generation of unstable truncated versions of these oncogenes. In certain cases, some of these truncated proteins could also act as stable dominant-negative variants and thus be anti-tumorigenic.
The current challenge for the biopharmaceutical community is to create ways to deliver these RNA-splicing compounds in effective doses in a targeted manner directly to cancer cells in vivo. If you are currently working in this area, we would welcome your perspective and feedback in the comments below.