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The UK NHS very recently approved a new cholesterol-lowering jab that will be offered to 300,000 people over the next three years.
The medicine – inclisiran – will be given twice a year as an injection.
It will be prescribed primarily to patients with a genetic disease causing high cholesterol, to those who have had a previous heart attack or stroke, or to those who have not responded well to other cholesterol-lowering drugs. , such as statins.
There has been a lot of enthusiasm around the drug’s approval, both because of what it may be able to accomplish and because the drug uses a technique known as ‘gene silencing’.
It 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 particular gene and preventing it from making the protein it produces.
Until now, most treatments using gene silencing technology have been used to treat rare genetic diseases. This means that the cholesterol jab will be one of the first gene silencing drugs used to treat people on a larger scale.
Researchers are also currently investigating whether gene silencing could be used to treat a wide variety of health problems, including Alzheimer’s disease and cancer.
Gene silencing
Gene silencing drugs 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 in our body because it copies and carries the genetic instructions of our DNA and makes specific proteins based on the instructions.
In the case of the cholesterol jab, gene silencing works by targeting a protein called PCSK9 and breaking it down. This protein is involved in the regulation of cholesterol in our body, but is present in excess in people with high levels of LDL cholesterol (the “bad” cholesterol). Preventing this protein from being produced 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 lab. This is a highly specific segment of RNA that can be used to target specific mRNAs.
In this case, the siRNA is designed to specifically target the mRNA that carries instructions for the PCSK9 protein. It binds to its target mRNA and destroys instructions, drastically reducing the amount of these proteins produced.
Gene therapies are usually given using a viral vector – a virus-like vehicle that delivers genes to our cells the same way a virus could infect them. Until now, viral vector therapies have been used to treat rare genetic blood disorders, genetic blindness and spinal muscular atrophy.
Although viral vectors are very effective with just one treatment, it may not be possible to give a second dose if necessary due to unwanted immune reactions. These drugs are also extremely expensive.
For this reason, many gene silencing drugs currently under investigation are administered using a different technique. Known as non-viral vector gene therapies, they deliver the drug using a nanoparticle that protects it from degradation in the blood so that it can be delivered specifically to the target – like the liver, which is the target of the cholesterol jab.
Gene silencing therapies delivered by non-viral vectors seem more promising because 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, the cholesterol jab is not buried inside a nanoparticle or delivered with a viral vector.
Instead, the siRNA has been heavily modified in the lab to resist degradation in the blood. It also has a ligand (a sugar molecule that works much like a hook) that allows it to specifically target liver cells.
Future treatments
Several other gene silencing drugs are currently being studied to treat a variety of other disorders, including in the kidneys (such as preventing side effects after a transplant), skin (scarring), cancer (including melanoma, prostate, pancreas, brain and other tumors) and eye disorders (such as age-related macular degeneration and glaucoma).
Researchers are also studying whether gene silencing therapies might 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 those of other drugs that exist today – by targeting a specific gene or protein and stopping it. But in the case of cancer, because it is very complex, it may be necessary to target several different proteins.
These gene silencing technologies will need to prove effective in further 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 remain low so that many people can access them. But overall, these developments hold great promise: gene silencing drugs are more specialized because they can target specific proteins in our cells.
Perhaps this is why they can be more effective in treating illnesses than current treatments.
Aristides Tagalakis, Reader in Gene Delivery and Nanomedicine, Edge Hill University.
This article is republished from The Conversation under a Creative Commons license. Read the original article.
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