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An important area of Isis' basic research is to understand the molecular mechanisms of antisense. There are at least 12 known antisense mechanisms that can be exploited once an antisense drug binds to its target RNA. Isis has created proprietary chemical modifications to trigger many of these mechanisms for drug discovery. As its understanding of these mechanisms further improves, the Company expects to develop antisense drugs with enhanced performance and for broader therapeutic applications.

An antisense mechanism is defined as the process in which an antisense drug works after it binds (hybridizes) to a target RNA to form a duplex. The formation of this duplex, or two-stranded molecule, prevents the RNA from functioning normally and from producing a protein.

Progress in Isis' mechanism of action research program is illustrated by the Company's accomplishments in understanding RNase H. The majority of late-stage antisense drugs in development bind to their target RNA and activate a cellular enzyme called RNase H. This enzyme destroys the target RNA, inhibiting production of a specific protein. Isis has cloned and characterized human RNase H and has effectively used that information to design its proprietary second-generation drugs. The Company expects to further improve its drugs, using its insights into the RNase H mechanism.

In addition to its RNase H expertise, Isis has made advancements in understanding and exploiting other antisense mechanisms.

RNA Interference (dsRNase, siRNA and RNAi)

Antisense drugs can be designed to bind to their target RNAs and recruit a different class of enzymes, called double-stranded RNases (dsRNase) that cleave the target RNA. There are many dsRNases in the cell, making this a potentially attractive mechanism. Isis' research led to one of the first scientific publications and key issued patents that address this mechanism. siRNAi and RNAi, for example, are dsRNase mechanisms that have received much attention in the drug discovery community. Isis has a strategic collaboration with a leader in RNAi therapeutics, Alnylam Pharmaceuticals, Inc. This alliance utilizes each company's intellectual property and expertise to expedite the development and commercialization of RNAi therapeutics.

Alternative Splicing

Alternative splicing has been shown to result in many diseases and accounts for most of the diversity in proteins. Alternative splicing is largely responsible for the functional complexity of the approximately 30,000-40,000 genes in the human genome; 40-60 percent of human genes have alternative splice forms.

Isis has pioneered the design of antisense drugs that can selectively direct alternative splicing to make one protein versus another.

The Role of MicroRNA

Researchers recently have discovered new families of natural antisense molecules made inside the cell called microRNAs; to date there are nearly 700 microRNAs that have been identified in the human genome, and these are believed to regulate the expression of approximately one-third of all human genes.  MicroRNAs are small RNA molecules that work as natural antisense oligonucleotides and appear to have critical functions in controlling the process of gene expression.  Isis scientists have been able to use microRNA in two ways. The first involves turning off, or inhibiting, genes in order to stop the production of a protein. The second involves turning on, or up regulating, genes so that specific proteins are made.

In September 2007, Isis and Alnylam Pharmaceuticals established Regulus Therapeutics Inc., a company focused on the discovery, development, and commercialization of microRNA-based therapeutics.  Regulus is addressing the therapeutic opportunities that arise from alterations in microRNA expression and advances on early work in microRNAs from both Isis and Alynlam scientists.

To date, microRNAs have been implicated in several disease areas, such as cancer, viral infection, and metabolic disorders.  Regulus is currently focusing on several of these disease areas.  More information on Regulus can be found on the Regulus website.