DNA base editing trials suspended due to side effects

US biotechnology company Verve Therapeutics has suspended patient enrollment in clinical trials of an experimental DNA base editing technique. This decision is due to severe side effects developed in one participant of the Phase Ib heart-1 trials. They are testing the safety and efficacy of the experimental drug VERVE-101 for the treatment of heterozygous hereditary hypercholesterolemia, in which a mutation in the PCSK9 gene causes low-density lipoprotein cholesterol (LDL-CS) levels to rise in the blood, leading to early atherosclerosis. A drug containing guide and matrix RNAs point-by-point replace one nitrogenous base in the gene being sought, turning it off completely. These RNAs are encapsulated in a liposomal shell that delivers them targeted to their site of action in liver cells.

According to interim results, the drug provided a persistent reduction in LDL-CS levels. At the same time, one of the patients developed a non-fatal myocardial infarction, the connection of which with the treatment experts could not exclude because of the proximity in time. The trial was not stopped because of this. However, another participant, who received a therapeutic dose of 0.45 milligrams per kilogram of body weight, had an increase in alanine aminotransferase (ALT) and thrombocytopenia during the first four days after administration, which were considered severe. After a few days, these events resolved without complications, but Verve, after consulting with an independent safety committee, decided to suspend enrollment until the causes of the side effects were clarified. Preliminary speculation suggests that the unwanted effects may be related to components of the liposomal shell of VERVE-101 nanoparticles.