Basic Science
Proteins are fundamental components of all living cells and include
many types of molecules necessary for carrying out the body’s
functions, such as enzymes, hormones and antibodies. The overproduction
or abnormal production of proteins is implicated or associated with
many diseases. The following paragraphs explain the process of protein
production and discuss how antisense prevents undesirable protein
production in disease.
Protein Production
Genes contain the information necessary to produce proteins. A gene
is made up of bases (Adenine, Thymine, Cytosine and Guanine commonly
refered to as A, T, C and G), which are linked together to form
a two-stranded structure that resembles a twisted ladder, known
as DNA (deoxyribonucleic acid). The nucleotides on one side of the
ladder interact with complementary nucleotides on the other side
of the ladder according to specific rules (A pairs with T, C pairs
with G), creating the ladder’s rungs. This highly specific
nucleotide binding is called hybridization. The sequence or order
of these nucleotides establishes the cell’s recipe for making
proteins.
One of the DNA strands is called the sense strand and the other
is called the antisense strand. A segment of a DNA helix might have
the following base pairing:
Protein production occurs in two phases called transcription and
translation. In the transcription phase, the DNA strand is used
as a template for manufacturing a RNA molecule. The RNA strand of
nucleotides is complementary to the DNA sense strand with one exception:
Uracil (U), instead of Thymine, is the base complementary to A.
Messenger RNA (mRNA) is responsible for communicating the genetic
message found in DNA to other areas of the cell so that protein
production can take place. Unlike DNA, mRNA is single-stranded and
able to leave the nucleus of the cell.
In the translation phase, the mRNA travels to the ribosome, which
is the cell’s machinery that assembles proteins based on the
instructions it carries.
Role of Antisense Technology
Antisense technology
interrupts the translation phase of the protein production process
by preventing the mRNA instructions from reaching the ribosome.
Isis’ antisense drugs are short, chemically-modified complementary
nucleotide chains that hybridize to a specific complementary area
of mRNA. Here’s an example:
When an antisense drug binds (hybridizes) to its target mRNA, the
mRNA is degraded and therefore is not translated by the ribosome
into a functional protein.
The mRNA is degraded through one of several mechanisms of action.
One antisense mechanism frequently used to degrade the target mRNA
is a natural enzyme called RNase H. RNase H is dispatched when a
DNA-like antisense drug hybridizes to its target mRNA, then cleaves
the target mRNA. The destruction of the mRNA inhibits production
of the protein encoded by that mRNA. By inhibiting the production
of proteins involved in disease, antisense drugs can create therapeutic
benefits for patients.
At least 12 known antisense mechanisms can be induced once an antisense
drug binds to its target RNA. Isis has created proprietary chemical
modifications to exploit 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.
