Basic Science

Antisense technology prevents the production of proteins involved in disease processes, which results in a therapeutic benefit to patients.

Proteins are fundamental components of all living cells and include many types of molecules, such as enzymes, hormones and antibodies, necessary for carrying out the body’s functions. The overproduction or abnormal production of proteins is implicated or associated with many diseases. 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 referred 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:

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Protein production occurs in two phases called transcription and translation. In the transcription phase, the DNA strand is used as a template for manufacturing an 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 carried by the mRNA.

Role of Antisense Technology

Antisense technology interrupts the translation phase of the protein production process by preventing the mRNA instructions from reaching the ribosome. Our antisense drugs are short, chemically modified complementary nucleotide chains that hybridize to a specific complementary area of mRNA. Here’s an example:

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When an antisense drug binds (hybridizes) to its target mRNA, the mRNA is degraded and therefore is not translated by the ribosome into a protein product.

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. RNase H finds this DNA-RNA hybrid and 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.

There are more than a dozen different antisense mechanisms that we can exploit with our antisense technology. The majority of the drugs in our pipeline bind to mRNAs and inhibit the production of disease-causing proteins. Our antisense technology is broadly applicable to many different antisense mechanisms, including RNA splicing, exon skipping, RNA interference, or RNAi, and enhancing protein translation to increase protein production.

Regulatory Role of RNAs

As discussed above, mRNAs are responsible for providing the blueprint for protein production. Most of the antisense drugs in our pipeline bind to mRNAs and inhibit the production of disease-causing proteins. Our SMA drug, IONIS-SMNRx, binds to the immature SMN2 (pre-mRNA) and promotes alternative splicing to increase production of the SMN protein. Our myotonic dystrophy drug, IONIS-DMPKRx, inhibits production of the toxic RNA. Recently the scientific community has discovered many new types of RNAs, including microRNAs and long non-coding RNAs, which are involved in the regulation of protein production within the cell. Our antisense technology is uniquely suited to exploit these exciting new RNA targets, as we have done with microRNAs through Regulus Therapeutics.

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