Gene silencing is a revolutionary medical technology that may unlock treatments and cures previously unimaginable. Genes are sections of DNA that contain the instructions for producing proteins. Proteins are essential molecules that carry out many bodily functions, from signal transmissions between cells to speeding up biochemical reactions to giving structural support for the cell.
Gene silencing is “an epigenetic modification of gene expression leading to inactivation of previously active genes.” That’s a mouthful but let’s break it down: Epigenetics is defined as modifications of DNA and its associated proteins and ribonucleoproteins that do not involve alterations in the DNA sequence itself.
So, gene silencing is not gene re-sequencing. It is, instead, a way to switch off troublesome DNA. Gene silencing is a natural process in normal development and differentiation to repress genes whose products are not required in specific cell types or tissues. This may apply to individual genes or larger chromosome regions.
Put another way, gene silencing targets or interferes with a specific gene and prevents its expression – meaning, the mechanism hinders or stops the production of a protein.
Each gene is responsible for producing a corresponding protein. The goal of gene silencing is to reduce or eliminate the production of a protein from its corresponding gene. The process involves two steps:
- Transcription – the information encoded in a gene is copied to the messenger RNA (mRNA) inside the cell’s nucleus (the cellular structure where all of the cell’s genetic material is contained).
- Translation – the mRNA subsequently travels out of the nucleus and carries the genetic information to produce a specific protein in a specific cell or group of cells.
Gene silencing interferes with gene expression before translation, unlike other approaches to genetic modification that directly edit DNA or inhibit the transcription process. In this way, a molecule designed to seek and destroy the gene-targeting mRNA (carrying instructions for making a specific protein), can effectively lower levels of that protein.
Being able to achieve significant reductions in targeted protein levels advances many opportunities in scientific research and pharmaceutical development since proteins are vital to the proper function and structure of cells.
There are two main types of gene silencing techniques – RNA interference (RNAi) and antisense oligonucleotides (ASOs) – among several others that all disable mRNA functioning by stopping it from being translated into a protein. These various methods use different designs for the molecule used to disrupt mRNA and the way mRNA breaks down. Consequently, different silencing methods have individual pros and cons.
Huntington’s Disease (HD) is a genetic disease due to the abnormal CAG (cytosine-adenine-guanine) expansion of the mutated HD protein (huntingtin) which instructs cells in the body to produce a version of the Huntington protein. Huntingtin is essential for neuronal death. In the brain, it causes the symptoms of HD.
While gene silencing holds promise for treating HD, many obstacles must be overcome before clinical use. Gene-silencing molecules must be directed and travel to the relevant parts of the body. In HD, the afflicted areas lie in the brain. The blood-brain barrier blocks most molecules that are injected or absorbed into the blood from passing through into the brain, making drug delivery difficult.
Then, gene-silencing molecules must locate neurons and other affected cells and penetrate those cells to prevent huntingtin expression. Complicating matters is that high dosages of silencing molecules have shown a toxic effect. Researchers are figuring out the best dosage, effective yet safe.
Another problem is that sometimes a false target is identified by the gene-silencing molecule which tries to bind with an undesired mRNA. Scientists hope to resolve off-target gene silencing by improving the selectivity of gene silencing drugs.
Speaking of gene silencing drugs, the FDA approved the first such medication in August 2018 from Alnylam Pharmaceuticals. Onpattro (also known as patisiran) is expected to cost $345,000 to $450,000 a year for the average polyneuropathy patient:
“The drug, which is dosed based on patient weight, was approved to treat polyneuropathy in patients with hereditary ATTR amyloidosis, a potentially fatal condition that affects an estimated 50,000 people worldwide.”
In ATTR amyloidosis, a genetic mutation stops a certain protein from maintaining its normal structure and makes it fold into an incorrect shape where it accumulates in the heart, nerves, and other organs. Loss of sensation, heart issues, and diseases of the eye, kidney, and thyroid can result.
One symptom of ATTR amyloidosis is polyneuropathy, the simultaneous malfunction of nerves, producing tingling, numbness, and kidney dysfunction.
Barry Greene, President of Alnylam, said:
“We are welcoming in an entirely new class of medicines. Over time, RNAi therapeutics will be incredibly impactful over a wide range of diseases.”
Ionis Pharmaceuticals and Arbutus Biopharma Corporation are also developing RNAi therapies. Alnylam is branching out into various other RNAi drugs to treat conditions ranging from high cholesterol to the genetic bleeding disorder hemophilia.