Download 14 Genes contain the information necessary to produce proteins. A

Genes contain the information necessary to produce proteins. A gene is made up of nucleoside bases: Adenine,
Thymine, Guanine, and Cytosine, commonly known as A, T, G and C, which are linked together to form a two-stranded
structure that resembles a twisted ladder, known as deoxyribonucleic acid, or DNA. The nucleotides on one side of the ladder
bind weakly to complementary nucleotides on the other strand according to specific rules; for example, A pairs with T and G
pairs with C, creating the ladder’s rungs. This highly specific nucleotide pairing is called hybridization. The sequence or
order of these nucleotides establishes the cell’s recipes for making proteins. Each protein’s instructions reside in a
corresponding segment of DNA known as a gene.
When a cell transcribes information from a DNA gene into messenger RNA or mRNA, the two complementary
strands of the DNA partly uncoil. One strand acts as a template and information stored in the DNA strand is copied into a
complementary mRNA. mRNA then carries the information to cellular structures called ribosomes, the cell’s factories for
manufacturing proteins. The ribosome reads the encoded information, the mRNA’s nucleotide sequence, and in so doing,
strings together amino acids to form a specific protein. This process is called translation. Antisense technology interrupts the
cell’s protein production process by preventing the RNA instructions from reaching the ribosome, thus inhibiting the
synthesis of the protein. The mRNA sequence of nucleotides that carries the information for protein production is called the
“sense” strand. The complementary nucleotide chain that binds specifically to the sense strand is called the “antisense”
strand. We use the information contained in mRNA to design chemical structures, called antisense oligonucleotides or
antisense drugs, which resemble DNA and RNA and are the complement of mRNA. These potent antisense drugs inhibit the
production of disease-causing proteins. Specifically, all of our antisense drugs in development cause a cellular enzyme called
ribonuclease H1, or RNase H1, to degrade the target mRNA. The drug itself remains intact during this process, so it can
remain active against additional target mRNA molecules and repeatly trigger their degradation. Our antisense drugs can
selectively bind to a mRNA that codes for a specific protein and will not bind to closely related RNAs, providing a level of
specificity that is better than traditional drugs. As a result, we can design antisense drugs that selectively inhibit the diseasecausing member of the group without interfering with those members of the group necessary for normal bodily functions.
This unique specificity means that antisense drugs may be less toxic than traditional drugs because we can design them to
minimize the impact on unintended targets.
Further, the design of antisense compounds is less complex, more rapid and more efficient than traditional drug
design directed at protein targets. Traditional drug design requires companies to identify a small molecule that will interact
with protein structures to affect the disease-causing process. Since predicting which small molecules will do this has proven
to be difficult, traditional drug discovery involves testing hundreds of thousands of small molecules for their ability to
interfere with protein function. As a result, traditional drug discovery is a labor intensive, low probability endeavor. In
contrast, we design our antisense compounds to bind to mRNA through well understood processes. We can design prototype
antisense drugs as soon as we identify the sequence for the target mRNA.
Using proprietary antisense oligonucleotides to identify what a gene does, called gene functionalization, and then
determining whether a specific gene is a good target for drug discovery, called target validation, are the first steps in our drug
discovery process. We use our proprietary antisense technology to generate information about the function of genes and to
determine the value of genes as drug discovery targets. Furthermore, because of the nature of antisense drugs, the very
molecules we design for gene functionalization and target validation experiments may become our lead drug candidates. This
efficiency is a unique advantage of our antisense drug discovery. Antisense core technology is the function within Isis that is
responsible for advancing antisense technology. Through the efforts of our scientists in the antisense core technology group,
we have produced second generation antisense drugs that have increased potency and stability. We combine our core
technology programs in medicinal chemistry, RNA biochemistry, and molecular and cellular biology with molecular targetfocused drug discovery efforts to design drugs. The goal of our target-based research programs is to identify antisense drugs
to treat diseases for which there are substantial markets and for which there is a need for better drugs. In addition, our
research programs focus on identifying next-generation compounds to serve as follow-on compounds to our current drugs in
development and to our development candidates.
Other Antisense Mechanisms
RNAi
In addition to advancing our RNase H1 mediated antisense drugs and core chemistries, we are also working to
understand the potential therapeutic utility of more nascent antisense mechanisms, including RNA interference, or RNAi, and
regulation of alternative splicing. For some of this research we work with satellite company partners, including Alnylam.
RNAi is an antisense mechanism that involves using small interfering RNA, or siRNA, as a method to target a
mRNA sequence. With siRNA, the cell utilizes a protein complex called RNA-induced silencing complex, or RISC, to bind
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