Dr. John Maraganore, CEO of Alnylam discusses RNA interference (RNAi), a breakthrough in understanding how genes are regulated in cells. It also represents a completely new approach to drug discovery and development.

5 Key Features of an RNAi Therapeutics Approach

1. The ability to harness a natural pathway. RNAi is a natural pathway involved in regulation of gene expression in all mammalian cells, and is mediated by small interfering RNA (siRNA) molecules. By harnessing this natural biologic pathway, RNAi therapeutics can be readily designed to be highly selective.

2. A catalytic mechanism. The RNA-Induced Silencing Complex (RISC) is an enzymatic complex that mediates mRNA silencing by RNAi that requires only a single siRNA to cleave a large number of target mRNAs. In other words, the actions of an siRNA are catalytic.

3. The ability to target virtually any protein. In contrast to small molecules and antibodies, it is possible to design siRNAs for the mRNA transcript of any gene. This capability suggests the possibility of developing RNAi therapeutics for proteins that do not fit into the so-called “druggable target classes.” Further, certain diseases may be caused by the mutation in one copy of the genetic material (a single allele), in which case a specific siRNA can target the disease-causing mutation and leave the normal allele intact. We believe that RNAi therapeutics can be designed to target any gene in the genome involved in the cause or pathway of disease.

4. Acting “upstream” of today’s medicines. The RNAi therapies we are developing have the potential to block the production of disease-causing proteins. With RNAi, we believe it may be possible to achieve a consistent and tunable level of disease protein knockdown, regardless of circulating blood levels, with the potential for disease control and intervention. By way of analogy, the RNAi approach is akin to stopping a flood “by turning off the faucet” as compared with today’s medicines that simply “mop up the floor.”

5. Simplifying the discovery of drug candidates. RNAi therapeutic drug candidates can be identified using bioinformatic tools to select sequences complementary to the target mRNA.

The process of choosing an RNAi-based drug candidate then involves the synthesis and testing of siRNAs. Further, siRNA lead candidates can be designed to be active across a broad range of species, potentially simplifying the translation of animal model data to human disease applications. In addition, certain chemical modifications can be applied to confer “drug-like properties” to siRNAs, making them stable when administered into the bloodstream. Finally, approaches for delivery of investigational RNAi therapeutics have now been engineered to enable a consistent level of target gene silencing in specific organs, such as genes expressed in the liver. At Alnylam Pharmaceuticals, Maraganore is helping lead the development of RNAi therapeutics which aim to address genetic medicines, cardio-metabolic diseases and hepatic infectious diseases.