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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 product. 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 is making significant advances in understanding this mechanism through funding from partners including Lilly. Isis also has a strategic collaboration with a leader in RNAi therapeutics, Alnylam Pharmaceuticals, Inc. This alliance will utilize each company's intellectual property and expertise to expedite the development and commercialization of RNAi therapeutics. Alternative Splicing DNA is composed of chains of nucleotides (abbreviated as A, C, T and G) that encode for proteins, as well as regions that are unnecessary for making proteins. Both the coding and non-coding regions are copied from DNA to RNA. The non-coding regions, called introns, must be deleted from the RNA strand. The process that removes these regions and reforms the finished RNA is called 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. Today, Isis continues its drug discovery and development partnerships with Ercole Biotech, a company focused specifically on this mechanism. In the future, many diseases may be amenable to this approach.
Researchers recently have discovered
new families of natural antisense molecules made inside the cell
called micro-RNAs; it is estimated there are hundreds of micro-RNA molecules in humans. These molecules appear to serve
as master regulatory molecules for many biological processes. Isis
scientists have been able to use micro-RNA in two ways. The first
involves turning off, or inhibiting, genes in order to stop the
production of a protein; an equivalent process to traditional antisense.
The second involves turning on, or up regulating, genes so that
specific proteins are made.
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