Coronary heart disease is the most common cause of death worldwide. It is caused by the narrowing of coronary arteries by the build-up of fatty material, atheroma, within the artery walls. Chest pain, owing to narrowing of coronary arteries, is known as angina, and complete blockage of the artery can cause heart attack (British Heart Foundation). Familial hypercholesterolemia (FH) is one of the main risk factors of coronary heart disease and is usually caused mutations in genes which encode proteins which are responsible for removing low density lipoprotein from circulation (Sjouke et al., 2011).
One of the main genes, identified as causative of FH in an autosomal dominant manner, is proprotein convertase subtilisin/kexin 9 (PCSK9) (Taranto et al. 2015). Mutations in this gene cause a gain of function. Serum levels of PCSK9 are positively associated with low-density lipoprotein (LDL) concentration, i.e. hypercholesterolemia, as well as phenotypic severity of coronary heart disease (Melendez et al., 2017).
Drug discovery for inhibitors of PCSK9 has led to the generation of 2 prominent drugs from Amgen, Repatha, and from Sanofi/Regeneron, Praluent. More recently a vaccine to inhibit PCSK9, AT04A has been developed which has been effective in mice (Laufs & Ference, 2017). This would be a more convenient mode of coronary heart disease prevention as just an annual booster vaccine would be required, rather than monthly dosing as with the aforementioned drugs. The molecule supplied in the vaccine stimulates the production of antibodies against the enzyme, which blocks PCSK9 and allows clearance of LDL, which lowers cholesterol. Mice induced with hypercholesterolemia and atherosclerosis from their diet displayed a 53% decrease in total cholesterol following subcutaneous injection of the vaccine. Now the vaccine is in phase I trials – which involves testing on 72 human volunteers and is due to be completed by the end of the year.
Ultimately this study has further proved that lowering cholesterol reduces the risk of coronary heart disease and therefore the importance of healthy lifestyle in conjunction with cholesterol reducing medications. The vaccine AT04A may be the way forward for lowering cholesterol and reducing the vast incidences of coronary heart disease in humans.
Blog written by Rachael Besser
Laufs & Ference, European Heart Journal (2017) 0, 1-3
Melendez et al., Archives of Biochemistry and Biophysics (2017) 625-626, 39-53
Sjouke et al., Curr. Cardiol. Rep., (2011) 13, 527-536
Taranto et al., Nutrition, Metabolism & Cardiovascular Diseases (2015) 25, 979-987
British Heart Foundation: https://www.bhf.org.uk/research/heart-statistics