Gene silencing: the basics

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Gene silencing is a relatively new treatment technique that makes use of the body’s natural processes to control disease by suppressing or ‘silencing’ specific genes that are associated with certain diseases. In this context, ‘silencing’ means temporarily blocking a specific gene’s message that would otherwise trigger an unwanted effect.

There are a number of different types of gene silencing methods. Silence Therapeutics is focusing on a biological process called RNA interference. RNA interference is a feature that all our bodies are born with and is designed to control the activity of the genes or defend the body against viruses.

Gene silencing is different from gene therapy. Gene therapy involves introducing new DNA into the body to permanently correct a missing or faulty gene. Gene silencing has a controllable, reversible effect which offers advantages if there are side effects. It is also highly specific and targeted, which means that the results are predictable.

Gene silencing is a fast-moving area of research. It has the potential to provide highly targeted treatments for specific genetic diseases as a potential lifelong treatment and has already been approved for some conditions (explored later in this eBook).

To understand gene silencing, it is useful to review the structure of a cell.

+What is the structure of a cell in the human body?

There are around 30-40 trillion cells in the human body. Each cell consists of an outer membrane (layer), a jelly-like substance called cytoplasm, and a center core or nucleus, which controls the activity of the rest of the cell. DNA (deoxyribonucleic acid), which contains the ‘genetic code’ of living things, is located in the nucleus. A gene is a small unit of DNA.

Human Cell

What are DNA and RNA?

In order to exist, a cell needs thousands of kinds of protein molecules. These are all “synthesized” (created) from the 20 amino acids which are present in all of nature and are known as the building blocks of life. To make a protein, a cell must put together a chain of amino acids in precisely the right order.

Every cell includes a quantity of nucleic acids, among them DNA (deoxyribonucleic acid) and RNA (ribonucleic acid). DNA, the carrier of genetic information, is enclosed in the central nucleus of a cell, whereas RNA is more widely distributed.

Genes are tiny units of DNA. They carry a coded form of the detailed instructions needed to produce proteins. A chromosome is a thread-like structure made up of hundreds of genes. The genome is the complete set of DNA found in an organism.

+A closer look at DNA

DNA contains the genetic code of organisms. It has all the instructions that a living organism needs to grow, reproduce and function. This information is contained in two chains that curl around each other to form a twisted ladder structure called a double helix.

The components of DNA can be arranged in an enormous number of combinations or sequences and each variation will produce a different type of protein. DNA determines the characteristics of an organism (living thing) – for example, the color of a person’s eyes or hair. With the exception of identical twins, each person’s DNA is unique.

DNA remains confined to the nucleus of the cell and it relies on another molecule, RNA, to deliver its instructions and translate them into action.

+A closer look at RNA

RNA is physically different from DNA. It contains only one single chain and is chemically more reactive than DNA. Unlike DNA, which is unable to leave the nucleus, RNA is more mobile and there are several different subtypes of RNA, which perform different functions.

RNA molecules ‘read’ the instructions provided by DNA, take a copy and activate the processes required to make them happen. When the instructions are turned into a functional product, such as a protein, this is called gene expression.

First the DNA is copied to make a matching RNA strand (transcription).

Then this is converted into proteins (translation).

Essentially RNA molecules use the blueprint provided by the DNA to instruct the amino acids on how to make the specified protein formation. These instructions are carried to other parts of the cell for processing by a type of RNA called messenger RNA (mRNA). It is mRNA that tells the cell which building blocks it should use to create the protein.

Gene Expression

Why is gene silencing treatment needed?

Sometimes the cell production process can become faulty and mistakes are made. For example, elements of DNA may be left out of the genetic instructions or cells may begin to mutate (change). Cells may produce too much of a particular protein or the protein it produces does not work correctly. This can lead to a variety of genetic diseases, including cystic fibrosis, Huntington’s disease, thalassemia, and some types of cancer. Some of these diseases are difficult to treat using conventional approaches. Gene silencing treatment offers a potential solution for conditions with a genetic cause.

What is RNAi?

RNA interference (RNAi) was a breakthrough discovery in the field of molecular biology in the late 1990s. The scientists who discovered it received the Nobel Prize in 2006. It is a control system that occurs naturally as part of the immune response. The immune response is the body’s defensive reaction to ‘invaders’ like viruses, bacteria and parasites.

Put simply, RNA molecules clear up mutations, correct mistakes and attack viruses that have infiltrated DNA. They are involved in the production of new proteins, but they can also work in reverse, moderating or adjusting the activity of the genes when needed. They reduce or block gene expression by ‘neutralizing’ targeted mRNA molecules and decreasing their activity. This is RNAi in action.

During RNAi, strands of RNA are divided or ‘diced’ into small pieces, which are called ‘small interfering RNAs’ (siRNA). These attach to mRNA targets and block their action, triggering the process of RNAi. This has the effect of ‘turning down’ or ‘silencing’ the production of the disease-associated protein, allowing the cell to revert to its normal healthy state.

+ How is RNAi used in gene silencing technology?

As we have seen, RNAi is a biological process, but it can also be deliberately triggered. The idea behind gene silencing is to intervene in the process of gene expression before translation takes place. Introducing an ‘anti-code’ designed to block problematic mRNA triggers the RNAi process, making it possible to ‘silence’ (temporarily switch off) specific disease-associated genes.

Gene silencing molecules are designed to mimic siRNA, allowing them to attach to specific parts of a gene in the same way, therefore blocking the gene’s message from being delivered. The key challenge is to deliver the siRNA-mimicking molecules to the target cells in an efficient and safe way.

By temporarily blocking a specific gene’s message, gene silencing molecules halt or reverse the progress of disease by targeting the underlying disease mechanism, rather than the symptoms it causes.

RNA Interference

Our approach to gene silencing at Silence Therapeutics >