US biotech Verve Therapeutics has for the first time shown that base editing can be used to turn off a gene in the liver in non-human primates. The trial was part of the company’s programme to create a ‘one-and-done’ gene editing treatment for lowering cholesterol.
Base editing is a technology that allows very accurate changes to be made to individual genes, without affecting the wider genome. ‘It’s very different from CRISPR Cas-9 technology, which is more like molecular scissors,’ explains Sekar Kathiresan, co-founder and CEO of Verve. ‘The analogy here is a pencil and eraser, where you can rub out one letter, and write in another.’
Verve has been trying out both technologies, and is looking at two different genes: PCSK9 and ANGPTL3. Both are known to cause increased blood levels of either LDL cholesterol or triglyceride-rich lipoproteins. Turning either off ought to give dramatic reductions in cholesterol levels in the bloodstream and therefore reduce the risk of coronary heart disease.
The idea, Kathiresan says, is to permanently turn one of these genes off in the liver. There is precedent that it should work, as there are already monoclonal antibodies that neutralise circulating PCSK9, and gene silencing technology using siRNA has also been successful. However, both require chronic medication; by editing the gene directly, a single treatment should suffice.
The base editing technology tested involves a guide RNA, which homes in on the right spot in the genome, and a piece of mRNA that does the actual gene editing. The two are packaged together in a lipid nanoparticle, which efficiently delivers them to the liver after injection.
In tests in monkeys, the genes were indeed turned off, and there were no detectable off-target edits. ‘We have done a lot of work to find the right combination of guide and editor,’ Kathiresan says. ‘We screened hundreds of guides to get the specific combination we needed.’
Turning off PCSK9, there was an 89% reduction in PCSK9 protein in the bloodstream, which gave a 59% reduction in blood cholesterol. And with ANGPTL3, there was a 95% fall in plasma protein, and a 64% reduction in blood cholesterol.
Verve should decide which approach to take forward as lead candidate by the end of 2020. ‘We hope to be in humans in late 2022 or early 2023,’ Kathiresan says. ‘We are evaluating multiple combinations of gene editor and guide RNA and also looking at CRISPR Cas-9 options.’
Both technologies have their strengths and weaknesses, he says. ‘We have been able to achieve similar levels of editing with both, but the two differ in a number of ways. These include the capacity of Cas-9 to generate double-strand breaks, and the capacity of the adenine base editor to edit RNA as well as DNA.’
The first patients to be treated, he expects, will be those with sky-high cholesterol levels despite standard of care treatment. ‘With sorting out the efficacy and safety in that group with that high unmet need, then we can move on to other, larger, patient populations,’ he says.