The UK NHS has very recently approved a new cholesterol-lowering blow that will be offered to 300,000 people over the next three years.
The drug, they will include, will be given twice a year as an injection.
It will be prescribed primarily to patients suffering from a genetic disease that leads to high cholesterol, to those who have already suffered a heart attack or stroke, or to those who have not responded well to other cholesterol-lowering medications, such as statins.
There has been a lot of excitement surrounding the drug’s approval, both for what it can achieve, and for the fact that the drug uses a technique known as “gene silence”.
This is an emerging therapeutic technique that works by targeting the underlying causes of a disease, rather than the symptoms it causes. It does this by targeting a specific gene and preventing it from producing the protein it produces.
Until now, most treatments that used gene silencing technology were used to treat rare genetic diseases. This means that cholesterol will be one of the first drugs to silence the genes used to treat people on a larger scale.
Currently, researchers are also investigating whether gene silencing could be used to treat a wide variety of diseases, including Alzheimer’s disease and cancer.
Silence of genes
Drugs that silence genes work by targeting a specific type of RNA (ribonucleic acid) in the body, called messenger RNA. RNAs are found in every cell in the body and play an important role in the flow of genetic information.
But messenger RNA (mRNA) is one of the most important types of RNA our body has, as it copies and carries genetic instructions from our DNA and makes specific proteins based on the instructions.
In the case of cholesterol, gene silencing works by targeting and degrading a protein called PCSK9. This protein is involved in the regulation of cholesterol in our bodies, but it is produced in excess in people with high levels of LDL cholesterol (the “bad” cholesterol). Preventing this protein from occurring in the first place will lower cholesterol levels.
In order to target this specific mRNA, researchers must create a synthetic version of another type of RNA, called small interfering RNA (siRNA), in the laboratory. This is a very specific stretch of RNA that can be used to target specific mRNAs.
In this case, the siRNA is designed to specifically target the mRNA containing instructions for the PCSK9 protein. It binds to its target mRNA and destroys the instructions, which significantly reduces the amount of these proteins that are produced.
Gene therapies are usually administered through a viral vector: a virus-like vehicle that delivers genes to our cells in the same way that a virus could infect them. To date, viral vector therapies have been used to treat rare genetic disorders of the blood, genetic blindness, and spinal muscular atrophy.
Although viral vectors are very effective with a single treatment, it may be impossible to administer a second dose if necessary due to adverse immune reactions. These medications are also extremely expensive.
Therefore, many of the drugs that silence the genes currently being researched are supplied with a different technique. Known as non-viral vector gene therapies, they supply the drug through a nanoparticle that protects it from blood degradation, so it can be administered specifically to the target, such as the liver, which is the target of cholesterol.
Gene silencing therapies administered by non-viral vectors appear to be more promising as they can be administered multiple times with limited side effects. Currently, non-viral vector therapies are used to treat a rare genetic condition called hereditary transthyretin-mediated amyloidosis, as well as in mRNA vaccines, such as BionTech / Pfizer and Moderna.
Interestingly, however, cholesterol is not buried within a nanoparticle nor is it delivered with a viral vector.
In contrast, siRNA has been extensively modified in the laboratory to withstand blood degradation. It also has a ligand (a sugar molecule that works a bit like a hook) connected that allows it to specifically target liver cells.
Future treatments
Various drugs are being investigated to silence genes to treat other disorders, including kidneys (such as preventing adverse reactions after a transplant), skin (scars), cancer (including melanoma, prostate, pancreas, brain and other tumors) and eye disorders (such as age-related macular degeneration and glaucoma).
Researchers are also investigating whether gene silencing therapies may be useful in treating neurological and brain disorders, such as Huntington’s disease and Alzheimer’s disease.
Each of these gene silencing treatments would use techniques similar to other drugs that currently exist, targeting a specific gene or protein and turning them off. But in the case of cancer, because it is so complex, it may be necessary to target several different proteins.
It needs to be shown that these gene silencing technologies are effective in other clinical trials before they can be deployed for use on a larger scale.
Another important challenge will be to ensure that the costs of these drugs are low so that many people can access them. But in general, these developments are very promising: drugs that silence genes are more specialized because they can target specific proteins in our cells.
This is why they may be more successful in treating diseases than current treatments.
Aristides Tagalakis, Lecturer in Gene Delivery and Nanomedicine, Edge Hill University.
This article is republished from The Conversation under a Creative Commons license. Read the original article.