The first ‘one-and-done’ base editing medicine in the human body has led to dose-dependent cholesterol reductions in people with genetically high levels of low-density lipoprotein cholesterol (LDL-c). Verve Therapeutics released human proof-of-concept data from a phase 1b trial designed to test whether a single-course in vivo base editing treatment, VERVE-101, can durably lower blood cholesterol by inactivating the gene for the proprotein convertase PCSK9 enzyme in the liver. People who are naturally resistant to atherosclerotic heart disease have rare inactivating genetic mutations in PCSK9 whereas in people with heterozygous familial hypercholesterolemia it is permanently switched on. The interim phase 1 results in 10 participants with an average 193 mg/dl LDL-c were reported at the conference of the American Heart Association. LDL-c was reduced by 55% in patients treated with the highest dose, 0.6 mg/kg body weight, and maintained at 6 months, and two patients treated with 0.45 mg/kg saw LDL reductions of 39–48%. But the trial also highlighted possible safety issues, as one patient had a non-fatal cardiac arrest that may have been treatment-related. Given the availability of pharmacological PCSK9 inhibitors, there are concerns that a gene-editing approach is risky. Monoclonal antibodies Praluent (alirocumab) from Sanofi and Regeneron and Repatha (evolocumab) made by Amgen, as well as the siRNA Leqvio (inclisiran) by Novartis, each lower LDL-c by about 50% in patients with familial hypercholesterolemia. Nevertheless, base editing — which does not make double-strand breaks — has potentially less scope for unintended genomic rearrangements than traditional CRISPR–Cas technology. VERVE-101 consists of an mRNA for adenine deaminase covalently linked to catalytically impaired Cas9 nickase and a guide RNA targeting PCSK9, contained in an engineered lipid nanoparticle. The adenine deaminase produces a A•T to G•C mutation at the target site. The trial of VERVE-101 is continuing. Verve also plans to test another adenine base editor mRNA plus gRNA packaged in N-acetylgalactosamine–lipid nanoparticles to turn off hepatic ANGPTL3 gene in patients with homozygous hypercholesterolemia.
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