RNAi (RNA Interference) is a new therapeutic strategy for treating many diseases, including cancers. RNAi offers important advantages over conventional treatments because it acts with high specificity and potency, as well as low toxicity. RNAi is a naturally occurring regulatory process in the body. Over the last decade, the understanding of human diseases has advanced enormously, and many genes that play fundamental roles in human diseases have been identified. Prior to the RNAi era, of the approximately 20,000 genes in the human genome, only 600-1,500 were considered “druggable,” those that could be targeted effectively with existing drug approaches, like small molecules or inhibitors and proteins such as monoclonal antibodies. The discovery of RNAi has potentially made every gene a druggable target.
The so-called “undruggable” targets are potentially accessible to small interfering RNAs (siRNAs) since siRNAs target the messenger RNAs and not the oncogene proteins. RNAi-based therapies show great promise in cancer treatment for a number of reasons, including:
• Ability to treat a broad range of diseases. siRNAs have the ability to silence virtually any gene to suppress the production of the related cancer-causing protein.
• Inherently potent and natural mechanism of action. siRNA cleaves messenger RNA and as a result halts production of specific proteins. Taking advantage of the body’s natural defense mechanism, we design our siRNAs to halt the production of specific cancer-causing proteins. We expect that this inherent catalytic nature of the RNAi mechanism will result in a high degree of potency and durability of effect for RNAi-based therapeutics. We believe that this distinguishes RNAi from other approaches, like antisense therapeutics, which are not catalytic and therefore require higher levels of drugs to achieve messenger RNA silencing. siRNA is a highly potent mechanism as each single siRNA molecule remains intact after inducing mRNA cleavage and serves for subsequent cycles of mRNA cleavage.
• Natural mechanism of action. Since RNA interference therapeutics harness a natural mechanism for gene silencing, we believe that this approach will demonstrate improved safety and tolerability as compared with other RNA-targeting approaches.
• Simplified discovery of product candidates. In contrast to the often arduous and slow drug discovery process for proteins and small molecules, we believe that the identification of siRNA product candidates will be much simpler, quicker and less costly because it involves relatively standard processes that are directed by the known gene target sequences and can be applied in a similar fashion to many successive product candidates.
Notwithstanding the promise of RNAi therapies, there remain a number of challenges. Key to the therapeutic application of siRNAs is the ability to successfully deliver siRNAs to target tissues and achieve cellular uptake of the siRNA into the inside of the cell where the RNAi machinery, called RNA-induced silencing complex, or RISC, is active.
In general, systemic delivery mechanisms of RNAi drugs, such as oral, intravenous and subcutaneous, need to shield the drug from the body’s natural defense response of enzyme-based degradation of such RNA molecules. Even if the drug leaves the blood stream and accesses the tumor, which is essential for effective action, effectiveness is limited by the high levels of collagen and the abnormally dense and opaque extracellular matrix that causes elevated pressure in the tumor core that in turn drives fluids outwards. Moreover, renal filtration, aggregation in the liver and other systemic effects significantly reduce the effective dose at the target site, which would raise the total dose needed to be administered, creating a risk of additional or more severe side effects. Recent approaches, including the use of nanoparticles and liposomes encompassing siRNAs, and Dynamic PolyConjugates (DPCs), have only proven to be partially effective because of non-targeting, clearance in the kidneys and the body’s natural defense mechanisms. As a result, systemic delivery of RNAi based drugs via intravenous, or other means, is largely limited to a small number of target tissues, in particular the liver.
In addition, direct injection of the pharmaceutical into the tumor without use of an implanted delivery platform, such as naked siRNA to topical targets (eye, skin, mucus membranes or local tumors) or intranasal/intratracheal instillation of aerosolized siRNA into the lung, are similarly less than optimally effective because of the need for repeated injections (about once per week) due to rapid dose decline by diffusion and degradation and, in some cases, such as in the tumor core, elevated pressure that expels the drug.