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

PCSK9 regulates LDL levels by promoting destruction of LDL receptors on liver cells, so overactive PCSK9 increases blood LDL while defective PCSK9 lowers it. PCSK9 has long been a drug target, and existing cholesterol therapies inhibit PCSK9 activity. VERVE-102 aims to permanently break the PCSK9 gene by using guide RNA to direct an adenine base-editing protein to change a single DNA base, creating a premature stop signal so the enzyme is not produced. In a dose-escalation trial, 35 patients received increasing doses from 0.3 mg/kg to 1 mg/kg. PCSK9 knockout and LDL reduction showed a dose response, with the lowest dose lowering PCSK9 by 51% and LDL by 9%, and the highest dose lowering PCSK9 by 88% and LDL by 62%.

"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."

Read at Ars Technica