In vivo CRISPR base editing of PCSK9 durably lowers cholesterol in primates
| Autor: | Kallanthottathil G. Rajeev, Nicole M. Gaudelli, Yusuf S. Nasrullah, Soumyashree A. Gangopadhyay, Andrew M. Bellinger, Sara P. Garcia, James Madsen, Jamie E. DeNizio, Athul Sanjeev, Lisa N. Kasiewicz, Giuseppe Ciaramella, Aaron Beach, Ellen Rohde, Anne Marie Mazzola, Thomas V. Colace, Kui Wang, Sowmya Iyer, Caroline W. Reiss, Padma Malyala, Steven H. Y. Fan, Victoria Clendaniel, Christopher J. Cheng, Jennifer Lavoie, Taiji Mizoguchi, Yuri Matsumoto, Madeleine Shay, Kiran Musunuru, Leslie E. Stolz, Maurine C. Braun, Chaitali Dutta, Ying K. Tam, Joseph Nneji, Ryan Garrity, Alexandra C. Chadwick, Souvik Biswas, Michael Amaonye, John D. Ganey, Mary R. Stahley, Huilan Ren, Huei-Mei Chen, Kathleen Berth, Sekar Kathiresan |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Male
0301 basic medicine Time Factors Genetic enhancement 030204 cardiovascular system & hematology Pharmacology Biology Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Genome editing Loss of Function Mutation In vivo Animals Humans CRISPR Gene Cells Cultured Gene Editing Gene knockdown Multidisciplinary Cholesterol Adenine PCSK9 Cholesterol LDL Mice Inbred C57BL Macaca fascicularis 030104 developmental biology Liver chemistry Models Animal Hepatocytes Mutagenesis Site-Directed Female CRISPR-Cas Systems Proprotein Convertase 9 |
| Zdroj: | Nature. 593:429-434 |
| ISSN: | 1476-4687 0028-0836 |
| DOI: | 10.1038/s41586-021-03534-y |
| Popis: | Gene-editing technologies, which include the CRISPR–Cas nucleases1–3 and CRISPR base editors4,5, have the potential to permanently modify disease-causing genes in patients6. The demonstration of durable editing in target organs of nonhuman primates is a key step before in vivo administration of gene editors to patients in clinical trials. Here we demonstrate that CRISPR base editors that are delivered in vivo using lipid nanoparticles can efficiently and precisely modify disease-related genes in living cynomolgus monkeys (Macaca fascicularis). We observed a near-complete knockdown of PCSK9 in the liver after a single infusion of lipid nanoparticles, with concomitant reductions in blood levels of PCSK9 and low-density lipoprotein cholesterol of approximately 90% and about 60%, respectively; all of these changes remained stable for at least 8 months after a single-dose treatment. In addition to supporting a ‘once-and-done’ approach to the reduction of low-density lipoprotein cholesterol and the treatment of atherosclerotic cardiovascular disease (the leading cause of death worldwide7), our results provide a proof-of-concept for how CRISPR base editors can be productively applied to make precise single-nucleotide changes in therapeutic target genes in the liver, and potentially in other organs. In a cynomolgus macaque model, CRISPR base editors delivered in lipid nanoparticles are shown to efficiently and stably knock down PCSK9 in the liver to reduce levels of PCSK9 and low-density lipoprotein cholesterol in the blood. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full text from SpringerLink