The prospects for a one-time treatment that reduces the risk of heart disease for the rest of a person鈥檚 life just got brighter. In an initial trial, a single dose of a CRISPR gene-editing therapy lowered cholesterol levels without any serious side effects.
The 鈥淗eart-2鈥� trial 鈥� organised by the biotech company Verve Therapeutics in Boston 鈥� involved 14 people who either had an inherited condition leading to very high cholesterol or had developed heart disease at a young age. While this was an early-stage trial that is mainly designed to test safety, the results indicate a clear dose-dependent effect.
The treatment, called Verve-102, involves a form of CRISPR gene editing called base editing. It is designed to alter a single DNA letter in the genomes of cells in the liver, switching off the production of a protein called PCSK9.
Advertisement
According to the company, in the four people given the lowest dose, levels of harmful low-density lipoprotein cholesterol (LDL-C) fell by an average of 21 per cent. For the six given a medium dose, LDL-C levels fell by 41 per cent, and for the four given the highest dose, they fell by 53 per cent.
鈥淭hese initial Heart-2 data are promising with respect to both safety and efficacy and suggest the potential for a new era of cardiovascular disease treatment, where a single dose might lead to lifelong control of LDL-C,鈥� at Harvard Medical School, an adviser to Verve, .
In 2005 it was discovered that people who don鈥檛 produce PCSK9 due to natural mutations have much lower cholesterol levels with no ill effects, leading to the development of drugs called PCSK9 inhibitors. While these are highly effective, they consist of large proteins called antibodies, meaning they are expensive and must be injected.
For this reason, statins remain the main drugs used to lower cholesterol levels, but they can have side effects, such as nausea and muscle pain. Half of people prescribed cholesterol-lowering drugs stop taking them after a year or so, according to Braunwald.
Verve-102 consists of mRNA coding for the base-editing machinery encapsulated in lipid nanoparticles, similar to mRNA vaccines. These lipid nanoparticles have been altered to avoid side effects seen with an earlier version of the treatment, called Verve-101. 鈥淪ome participants in the original trial had blood tests suggesting liver issues, but that seems not to have happened with the new formulation,鈥� says science writer , who studies ageing.
Halving LDL-C means this dosage of Verve-102 works about as well as PCSK9 inhibitor treatments, he says. 鈥淔or a small trial, this is a pretty good result. Because the effect is so large and the mechanism is so clear, I think we can be reasonably confident that this treatment will work.鈥�
In theory, there is a small risk of unwanted changes to the DNA of cells, which in the worst-case scenario could lead to cancer. 鈥淔or patients struggling with inherited high cholesterol and significantly increased risk of heart disease, stroke and so on, this could well be a risk worth running,鈥� says Steele. 鈥淚t will probably be quite a few years before we can be absolutely sure these new treatments are safe.鈥�
Other teams are trying develop treatments that turn off the PCSK9 gene without altering its DNA sequence, which would avoid the risk of unwanted DNA changes, but these treatments are also still at an early stage.
