Luk H. Vandenberghe

Luk H. Vandenberghe, Ph.D., is Director of the Grousbeck Gene Therapy Center at Massachusetts Eye and Ear and Associate Professor of Ophthalmology at Harvard Medical School. His laboratory deconstructs viral evolution to improve viral vector design and application in gene therapy. Dr. Vandenberghe is internationally recognized for pioneering ancestral AAV (AncAAV) technology through evolutionary-guided vector design. Using computational ancestral sequence reconstruction, his team inferred the evolutionary history of AAV and resurrected extinct ancestral viral capsids. Published in Cell Reports in 2015, this groundbreaking work generated nine functional putative ancestral AAVs and identified Anc80—the predicted common ancestor of widely studied AAV serotypes 1, 2, 8, and 9—as a highly potent gene therapy vector for targeting liver, muscle, and retina. Unlike contemporary AAV serotypes to which human populations have been exposed, ancestral viruses may elicit lower pre-existing immune responses while demonstrating broader tissue tropism and enhanced transduction efficiency. AncAAV technology has been licensed by multiple companies and is progressing into clinical applications for various diseases. Beyond rational vector design, Vandenberghe's laboratory has systematically elucidated AAV cellular entry mechanisms. In 2020, his team discovered GPR108 (a G protein-coupled receptor superfamily member) as the second essential AAV entry factor conserved between mice and humans. Using genome-wide CRISPR knockout screens, Vandenberghe identified distinct AAV lineages that utilize different receptor combinations: while most AAV serotypes depend on AAVR plus GPR108, AAV4 and AAVrh32.33 can transduce cells independently of AAVR. His directed evolution studies revealed "receptor switching" phenomena, whereby evolved AAV variants acquire the ability to recognize alternative receptors such as integrin β1 (ITGB1) or sulfated glycosaminoglycans. These mechanistic insights into AAV-host interactions explain tissue tropism differences across serotypes and provide theoretical foundations for engineering AAV variants with enhanced specificity, immune evasion, or novel targeting capabilities. Vandenberghe's 2022 Trends in Molecular Medicine review with Zolotukhin frames AAV capsid engineering as a "Goldilocks challenge"—balancing targeting specificity, safety, and therapeutic durability.

Luk H. Vandenberghe哲学博士，是麻省眼耳医院Grousbeck基因治疗中心主任和哈佛医学院眼科学副教授。他的实验室解构病毒进化以改进病毒载体设计和基因治疗应用。 Vandenberghe博士国际公认为通过进化引导的载体设计开创祖先AAV (AncAAV)技术的先驱。使用计算祖先序列重建，他的团队推断AAV的进化历史并复活了已灭绝的祖先病毒衣壳。2015年发表在Cell Reports的这项开创性工作产生了9个功能性推定祖先AAV，并鉴定出Anc80——广泛研究的AAV血清型1、2、8和9的预测共同祖先——作为靶向肝脏、肌肉和视网膜的高效基因治疗载体。与人群已暴露的当代AAV血清型不同，祖先病毒可能引起较低的预存免疫反应，同时展示更广泛的组织趋向性和增强的转导效率。AncAAV技术已被多家公司授权，正在推进到各种疾病的临床应用。 除了理性载体设计，Vandenberghe实验室系统地阐明了AAV细胞进入机制。2020年，他的团队发现GPR108（G蛋白偶联受体超家族成员）作为小鼠和人类之间保守的第二个必需AAV进入因子。使用全基因组CRISPR敲除筛选，Vandenberghe鉴定出使用不同受体组合的不同AAV谱系：虽然大多数AAV血清型依赖AAVR加GPR108，但AAV4和AAVrh32.33可以独立于AAVR转导细胞。他的定向进化研究揭示了"受体转换"现象，即进化的AAV变体获得识别替代受体（如整合素β1 (ITGB1)或硫酸化糖胺聚糖）的能力。 这些对AAV-宿主相互作用的机制见解解释了血清型之间的组织趋向性差异，并为工程化具有增强特异性、免疫逃避或新型靶向能力的AAV变体提供了理论基础。Vandenberghe与Zolotukhin 2022年在Trends in Molecular Medicine的综述将AAV衣壳工程框架为"金发姑娘挑战"——平衡靶向特异性、安全性和治疗持久性。