That target gene is one that codes for proprotein convertase subtilisin/kexin type 9 (PCSK9). This enzyme plays a role in regulating LDL levels in the blood. Specifically, it promotes the destruction of LDL receptors on liver cells that would otherwise help clear LDL from circulation. Thus, people who have an overactive version of PCSK9 have fewer LDL receptors, and have higher levels of LDL in their blood. Those who have defective versions of PCSK9 have lower levels of LDL. This has been known for years, making PCSK9 a well-established target. Many drugs already in use to treat high cholesterol work by inhibiting PCSK9.
However, with VERVE-102, the goal is to permanently break the gene that encodes PCSK9. Specifically, the guide RNA directs the adenine base-editing protein to change a single base in the PCSK9 gene, causing the cellular machinery to read the stop signal prematurely, and the enzyme is not produced.
In the trial, the first 35 patients were given different doses so researchers could gradually test the safety. The first four participants started with the lowest dose of 0.3 mg per kilogram of body weight. When this was cured, another subgroup of six received 0.45 mg/kg. Others were then given higher doses of 0.6 mg/kg, 0.7 mg/kg, 0.8 mg/kg and a final higher dose of 1 mg/kg, which was given to seven participants. The first subgroup, which received the lowest dose, was followed for 18 months, while the subgroup receiving the highest dose was followed so far for only three months.
The researchers observed a dose response in both the amount of PCSK9 and the size of the reduction in LDL caused by the treatment; The larger the dose, the lower PCSK9 and the lower LDL. For the lowest dose, average PCSK9 levels fell 51 percent, while average LDL fell 9 percent. For the highest dose, average PCSK9 levels fell 88 percent and average LDL fell 62 percent.
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