In the United States, around 500,000 people are expected to die of coronary artery disease this year. Coronary artery disease is the most common form of heart disease. CAD occurs when arteries supplying blood to the heart become hardened and narrowed due to the buildup of cholesterol. Over time, heart muscle weakens. That leads to heart failure.
People with high blood cholesterol can make lifestyle changes to reduce their cholesterol level and physicians can prescribe statins to lower levels of LDL cholesterol – often referred to as bad cholesterol. While statins are effective and have saved the lives of millions of Americans, they are not without side effects.
However, an alternative treatment could well be on the horizon. It could be administered with a single injection and could serve as a life-long treatment to prevent LDL cholesterol from ever rising to dangerous levels.
The treatment would involve the delivery of CRISPR-Cas9 – a pairing of guide RNA and a DNA cutting enzyme. CRISPR-Cas9 is a novel gene editing tool that has been shown to allow the precise editing of DNA in animal studies. The tool can be used to make precise cuts in the DNA allowing new sections to be inserted, mutations to be removed, or genes to be otherwise altered.
The gene-editing technique has shown tremendous potential for safely making alterations to DNA, and while the technique is not yet being used in clinical trials on humans, a number of clinical trials are expected to begin this year.
Pharma giant AstraZeneca, like many pharmaceutical firms, is particularly interested in the CRISPR system. CRISPR could well serve as an alternative to the use of pharmaceutical products for the treatment of disease. The company is closely following the latest research and has its own research team working on the gene-editing technique.
At a genomics meeting in London earlier this month, AstraZeneca’s Lorenz Mayr – who leads the company’s CRISPR research team – explained the potential of the gene editing system for providing preventative treatment against high cholesterol. Instead of waiting until LDL cholesterol reaches dangerous levels, CRISPR could be used to make a change to the DNA that would help to ensure LDL cholesterol levels remain permanently low.
Just over 10 years ago, researchers discovered that many of individuals with low cholesterol levels had a genetic mutation that prevents the synthesis of a protein called PCSK9. PCSK9 is synthesized in the liver and released into the blood stream. PCSK9 degrades a protein found on the surface of blood vessels, however that protein removes LDL cholesterol from the blood. Without PCSK9, cholesterol is removed quickly. If levels of PCKS9 are high, LDL cholesterol builds up.
Individuals with the genetic mutation that prevents the synthesis of PCKS9 appear to suffer no ill effects. Consequently, if the same genetic mutation can be triggered in normal individuals, the result will be the same. No PCKS9. No high cholesterol.
Unsurprisingly, researchers have worked at developing antibody drugs that remove PCKS9 from the blood. There are no apparent side effects and the drugs reduce LDL cholesterol; however, the drugs are extremely expensive and need to be used on a regular basis. Consequently, they are prohibitively expensive for widespread use.
CRISPR on the other hand could potentially be used as an alternative treatment. It is both cheap and effective and while there are potential side effects – unintended gene cuts – research appears to show that the technique is safe to use.
At Mayr’s laboratory at AstraZeneca, CRISPR has been used to disable PCKS9 in mice. Perhaps even better news is that the CRISPR treatment was shown to be even more effective than treatment with the antibody drugs.
A one-off LDL cholesterol injection may be some way off, but the potential of the CRISPR systems is clear. In a few years, it may be possible to protect a whole generation from developing high cholesterol levels and millions of lives could be saved.