US biotechnology company Verve Therapeutics has published its preclinical, proof-of-concept paper on the successful use of base editing to turn off a gene in the liver and thereby lower blood levels of either LDL cholesterol or triglyceride-rich lipoproteins, two factors leading to coronary atherosclerosis. The paper was published in the 20th May edition of Nature —https://www.nature.com/— The paper establishes that gene-editing technologies, which include the CRISPR–Cas nucleases and CRISPR base editors, have the potential to permanently modify disease-causing genes in patients.
Future Medicine India had in its August-’20 edition reported Verve’s first presentation of its data on this research.
The paper reports that the demonstration of durable editing in target organs of nonhuman primates is a key step before in vivo administration of gene editors to patients in clinical trials. The company said it has demonstrated that CRISPR base editors that are delivered in vivo using lipid nanoparticles can efficiently and precisely modify disease-related genes in living cynomolgus monkeys (Macaca fascicularis).
“We observed a near-complete knockdown of PCSK9 in the liver after a single infusion of lipid nanoparticles, with concomitant reductions in blood levels of PCSK9 and low-density lipoprotein cholesterol of approximately 90% and about 60%, respectively; all of these changes remained stable for at least 8 months after a single-dose treatment,” the authors wrote in the paper.
In addition to supporting a ‘once-and-done’ approach to the reduction of low-density lipoprotein cholesterol and the treatment of atherosclerotic cardiovascular disease (the leading cause of death worldwide), the results provide a proof-of-concept for how CRISPR base editors can be productively applied to make precise single-nucleotide changes in therapeutic target genes in the liver, and potentially in other organs, added the authors.