Targeted strike on hypercholesterolemia

Single–nucleotide editing is a new approach to gene editing that allows you to change nucleotides – the smallest units of the DNA structure. An international research team led by the University of Zurich identified a mutation in a certain gene responsible for cholesterol levels, and using single-nucleotide editing, achieved its steady decrease in the blood of mice and macaques.

Lipoproteins are complex particles that deliver fat molecules through blood vessels to all tissues of the body, supplying cells with energy. One type of lipoprotein, low-density lipoprotein (LDL), can transport thousands of molecules, including cholesterol, per particle. High levels of LDL in the blood are clinically associated with an increased risk of cardiovascular diseases. Since LDL also carries cholesterol into smaller vessels to supply energy to more distant tissues, they can block the lumen of the arteries, leading to atherosclerosis.

One gene mutation blocks an enzyme

The research team has demonstrated that a new precise approach to gene editing can significantly and sustainably reduce high LDL levels. Using single-nucleotide editing, the scientists produced a single point mutation in the gene encoding the PCSK9 enzyme. This protein is involved in the delivery of LDL cholesterol from the blood to the cells.

The genetic changes that the researchers induced in mice and macaques successfully blocked PCSK9, which led to a significant decrease in the concentration of LDL cholesterol in the blood. Potentially, such therapy will help patients suffering from familial hypercholesterolemia, a hereditary form of high cholesterol.

Adaptation of RNA technology used in COVID-19 vaccines

The gene editing technology used by the researchers uses so-called single-nucleotide editors. These proteins can change the individual nitrogenous bases of the DNA molecule – one letter of the genetic code to another. Adenine base editors, for example, convert adenine (A) to guanine (G). And single-nucleotide editors do this much more precisely than CRISPR/Cas nucleases, which function as molecular scissors.

To control the delivery of the editor protein to the liver of animals, the researchers adapted the RNA technology used in some COVID-19 vaccines: instead of the RNA encoding the spike protein SARS-CoV2, they encapsulated the RNA encoding the adenine base editor protein into lipid nanoparticles.

Accurate, efficient and safe

Preparations of RNA-lipid nanoparticles were injected into animals intravenously, they accumulated in liver cells and produced an editor protein.

Up to two-thirds of PCSK9 genes were edited in mice and up to one-third in non-human primates, which led to a significant reduction in LDL cholesterol levels. In addition, the scientists carefully assessed whether editing occurred outside the target areas, but found no signs of such undesirable events.

RNA therapy of metabolic liver diseases

Approximately 30% of all hereditary mutations that cause diseases are single nucleotide mutations that can be corrected using single nucleotide editors. Thus, the new approach is potentially effective for the treatment of a large number of patients suffering from hereditary metabolic liver diseases, such as hypercholesterolemia, phenylketonuria or urea cycle disorders. Compared to conventional drugs, genome editing has the advantage that the induced changes are stable, that is, if the mutation occurs in a sufficient number of cells, the patient will be cured forever.

Article by T.Rothgangl et al. In vivo adenine base editing of PCSK9 in macaques reduces LDL cholesterol levels is published in the journal Nature Biotechnology.

Aminat Adzhieva, portal "Eternal Youth" http://vechnayamolodost.ru based on the materials of UZH: Cholesterol Levels Sustainably Lowered Using Base Editing.