Verve Therapeutics reported the results of clinical trials of the drug VERVE-102 for the treatment of genetic hypercholesterolemia. Its action is based on CRISPR/Cas technology. With its help, it was possible to inactivate the defective gene and the level of "bad" cholesterol in patients decreased by 21-53 percent depending on the dose of the drug. No serious side effects were found in the therapy.
Heterozygous familial hypercholesterolemia (HeFH) is an autosomal dominant disorder in which a mutation in one gene causes the blood to have elevated levels of “bad” cholesterol (low-density lipoprotein, LDL). The disease is asymptomatic for a long time, and many patients therefore do not receive any treatment. Accelerated cholesterol deposition in the 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 binding of PCSK9 to the LDL receptor leads to its degradation. A decrease in the level of LDL receptors, in turn, reduces LDL metabolism, which leads to hypercholesterolemia. In 2023, the American biotechnology company Verve Therapeutics completed the first clinical trials of the drug VERVE-101, based on CRISPR/Cas technology. The guide RNA in it recognizes the desired sequence in the PCSK9 gene, and the messenger RNA encodes the ABE protein, which replaces adenine with guanine in one place, which ultimately completely turns off the gene.
Along the way, the company was 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 lacking LDL receptors due to homozygous familial hypercholesterolemia. In a press release on its website, the company announced the completion of clinical trials of VERVE-102.
The study involved 14 people with HeFH or early ischemic heart disease. The patients were divided into three groups depending on the dose of the drug: 0.3 milligrams per kilogram of body weight (4 people), 0.45 milligrams per kilogram of body weight (6 people), and 0.6 milligrams per kilogram of body weight (4 people). The drug was administered by a single injection. The participants were monitored for at least a month and no serious side effects were found, and in addition, no cardiovascular complications were recorded. One of the participants developed a non-specific reaction to the injection, which was stopped 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 seen in the 0.6 milligrams per kilogram of body weight group: 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 of 0.7 milligrams per kilogram of body weight. The results of the clinical trials are planned to be released in late 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 began to better distinguish light sources and navigate in space.