Verve Therapeutics reported the results of clinical trials of VERVE-102, a drug for the treatment of genetic hypercholesterolemia. It uses CRISPR/Cas technology. It successfully inactivated the defective gene, reducing patients' LDL cholesterol levels by 21-53 percent, depending on the dose. No serious side effects were observed.
Heterozygous familial hypercholesterolemia (HeFH) is an autosomal dominant disorder in which a mutation in a single gene causes elevated levels of "bad" cholesterol (low-density lipoprotein, or LDL) in the blood. The disease is asymptomatic for many years, and therefore many patients receive no treatment. Accelerated cholesterol deposition in arterial walls leads to early heart attacks and strokes.
Up to five percent of HeFH cases develop due to a mutation in proprotein convertase subtilisin-kexin type 9 (PCSK9). Excessive PCSK9 binding to the LDL receptor leads to its degradation. Reduced LDL receptor levels, in turn, reduce LDL metabolism, leading to hypercholesterolemia. In 2023, the American biotechnology company Verve Therapeutics completed the first clinical trials of VERVE-101, a drug based on CRISPR/Cas technology. Its guide RNA recognizes a target sequence in the PCSK9 gene, and the messenger RNA encodes the ABE protein, which replaces adenine with guanine at one site, ultimately completely disabling the gene.
The company was simultaneously developing an improved drug, VERVE-102, which also inactivates PCSK9, but its RNA is packaged in a proprietary liposomal shell, GalNAc-LNP, which ensures delivery to liver cells deficient in LDL receptors due to homozygous familial hypercholesterolemia. In a press release on its website, the company announced the completion of clinical trials for VERVE-102.
The study involved 14 people with HeFH or early coronary artery disease. The patients were divided into three groups based on the drug dose: 0.3 milligrams per kilogram of body weight (4 patients), 0.45 milligrams per kilogram of body weight (6 patients), and 0.6 milligrams per kilogram of body weight (4 patients). The drug was administered via a single injection. The participants were monitored for at least a month and no serious adverse effects were observed, nor were any cardiovascular complications recorded. One participant developed a nonspecific injection reaction, which was treated with paracetamol.
The researchers observed a dose-dependent effect of the treatment. In the 0.3 milligrams per kilogram of body weight group, LDL-C decreased by 21 percent, and PCSK9 by 46 percent. In the 0.45 milligrams per kilogram of body weight group, LDL-C decreased by 41 percent, and PCSK9 by 53 percent. The greatest reduction was achieved in the group receiving 0.6 milligrams per kilogram of body weight: 53 percent for LDL-C and 60 percent for PCSK9.
The company is currently recruiting patients to test the drug at an even higher dose—0.7 milligrams per kilogram of body weight. Clinical trial results are planned to be released by the end of 2025.
The CRISPR/Cas system has already been successfully used to treat other diseases, such as congenital retinal dystrophy. As a result, two out of five patients improved their ability to distinguish light sources and navigate spatially.
