Bad cholesterol slashed 62% by single dose of gene-editing drug in small trial

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 overactive versions of PCSK9 have fewer LDL receptors, and higher LDL levels in their blood. Those who have defective versions of PCSK9 have lower LDL levels. This has been known for years, making PCSK9 a well-established target. Multiple drugs already in use for treating high cholesterol work by hobbling PCSK9.

With VERVE-102, though, 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 such that it causes cellular machinery to prematurely read a stop signal, and the enzyme is not produced.

In the trial, the first 35 patients were given different doses so researchers could gradually test safety. The first four participants started with the lowest dose of 0.3 mg per kilogram of body weight. When that went well, a second subgroup of six got 0.45 mg/kg. Then others got 0.6 mg/kg, 0.7 mg/kg, 0.8 mg/kg, and the final high dose of 1 mg/kg, which was given to seven participants. The first subgroup that got the lowest dose was followed for 18 months, while the subgroup that got the highest dose was followed for just three months so far.

The researchers noted a dose response in both the amount of PCSK9 the treatment knocked out and the size of the LDL reduction; the larger the dose, the less PCSK9, and the lower the LDL. For the lowest dose, mean PCSK9 levels dropped 51 percent, while mean LDL dropped 9 percent. For the highest dose, mean PCSK9 levels dropped 88 percent with mean LDL dropping 62 percent.