Mark A. Kay

Mark A. Kay, M.D., Ph.D., is the Dennis Farrey Family Professor of Pediatrics and Professor of Genetics at Stanford University School of Medicine, where he serves as Associate Chair for Basic Research in the Department of Pediatrics and Director of the Division of Human Gene Therapy. He holds memberships across multiple Stanford institutes including Bio-X, the Cancer Institute, and the Wu Tsai Neurosciences Institute. Dr. Kay is a pioneer in AAV-mediated liver-directed gene therapy, particularly for hemophilia. His laboratory conducted landmark clinical trials in the early 2000s that first demonstrated AAV-mediated factor IX expression in hemophilia B patients. Through portal vein and hepatic artery delivery of AAV vectors, Kay's team achieved therapeutic factor IX levels, though immune responses initially limited durability to approximately eight weeks. These studies provided critical insights into host immune barriers that informed subsequent therapeutic developments. Kay's seminal work on computationally designed liver-specific promoters revolutionized hepatic gene therapy. His laboratory established design principles for tissue-specific transcriptional modules that have been widely adopted in preclinical and clinical AAV studies. Kay discovered and validated the "liver tolerance effect"—the phenomenon whereby AAV liver gene therapy induces immune tolerance to the transgene product—first demonstrated in hemophilia B mice achieving tolerance to human factor IX. Kay developed AAV serotype 8 (AAV8) approaches for liver gene therapy, achieving 1-6% normal factor IX expression levels in severe hemophilia B clinical trials. His innovations provided technological foundations for FDA-approved hemophilia gene therapies including Etranacogene Dezaparvovec (Hemgenix), Beqvez, and Roctavian. Beyond AAV vectors, Kay's laboratory investigates non-coding RNA therapeutics, discovering mechanisms of miRNA loading into RISC complexes and identifying novel small RNA classes derived from tRNA and other non-coding sources. In 2025, Kay co-authored a comprehensive Molecular Therapy review surveying past achievements and future prospects in liver-directed gene therapy, continuing his leadership in advancing genetic medicines for hepatic diseases.

Mark A. Kay医学博士、哲学博士，是斯坦福大学医学院Dennis Farrey家族儿科教授和遗传学教授，担任儿科系基础研究副主任和人类基因治疗部主任。他是斯坦福Bio-X、癌症研究所和吴蔡神经科学研究所的成员。 Kay博士是AAV介导的肝脏靶向基因治疗先驱，特别是在血友病领域。他的实验室在2000年代初期进行了里程碑式的临床试验，首次证明了血友病B患者中AAV介导的凝血因子IX表达。通过门静脉和肝动脉递送AAV载体，Kay团队达到了治疗水平的因子IX表达，尽管免疫反应最初将持续时间限制在约8周。这些研究为理解宿主免疫屏障提供了关键见解，指导了后续治疗的发展。 Kay在计算设计肝脏特异性启动子方面的开创性工作革新了肝脏基因治疗。他的实验室建立了组织特异性转录模块的设计原则，被临床前和临床AAV研究广泛采用。Kay发现并验证了"肝脏耐受效应"——AAV肝脏基因治疗诱导对转基因产物免疫耐受的现象——首次在血友病B小鼠中证明对人凝血因子IX产生耐受。 Kay开发了AAV血清型8 (AAV8)肝脏基因治疗方法，在严重血友病B临床试验中达到1-6%正常因子IX表达水平。他的创新为FDA批准的血友病基因治疗提供了技术基础，包括Etranacogene Dezaparvovec (Hemgenix)、Beqvez和Roctavian。 除了AAV载体，Kay实验室还研究非编码RNA治疗学，发现miRNA装载进RISC复合物的机制，识别出源自tRNA和其他非编码序列的新型小RNA类别。2025年，Kay合著了Molecular Therapy综述，总结肝脏靶向基因治疗的过去成就和未来前景，继续领导肝脏疾病遗传药物的推进。