クーリャル　シモン   KURIAL　SIMONE    所属   川崎医科大学  医学部 基礎医学　解剖学    職種   特任講師
論文種別	原著
言語種別	英語
査読の有無	査読あり
表題	AAV capsid prioritization in normal and steatotic human livers maintained by machine perfusion.
掲載誌名	正式名：Nature biotechnology 略　 称：Nat Biotechnol ISSNコード：15461696/10870156
掲載区分	国外
著者・共著者	Jae-Jun Kim, Simone N T Kurial, Pervinder K Choksi, Miguel Nunez, Tyler Lunow-Luke, Jan Bartel, Julia Driscoll, Chris L Her, Simaron Dhillon, William Yue, Abhishek Murti, Tin Mao, Julian N Ramos, Amita Tiyaboonchai, Markus Grompe, Aras N Mattis, Shareef M Syed, Bruce M Wang, Jacquelyn J Maher, Garrett R Roll, Holger Willenbring
担当区分	筆頭著者
発行年月	2025/01
概要	Therapeutic efficacy and safety of adeno-associated virus (AAV) liver gene therapy depend on capsid choice. To predict AAV capsid performance under near-clinical conditions, we established side-by-side comparison at single-cell resolution in human livers maintained by normothermic machine perfusion. AAV-LK03 transduced hepatocytes much more efficiently and specifically than AAV5, AAV8 and AAV6, which are most commonly used clinically, and AAV-NP59, which is better at transducing human hepatocytes engrafted in immune-deficient mice. AAV-LK03 preferentially transduced periportal hepatocytes in normal liver, whereas AAV5 targeted pericentral hepatocytes in steatotic liver. AAV5 and AAV8 transduced liver sinusoidal endothelial cells as efficiently as hepatocytes. AAV capsid and steatosis influenced vector episome formation, which determines gene therapy durability, with AAV5 delaying concatemerization. Our findings inform capsid choice in clinical AAV liver gene therapy, including consideration of disease-relevant hepatocyte zonation and effects of steatosis, and facilitate the development of AAV capsids that transduce hepatocytes or other therapeutically relevant cell types in the human liver with maximum efficiency and specificity.
DOI	10.1038/s41587-024-02523-6
PMID	39881029