Dirk Grimm

Dirk Grimm, Ph.D., is Professor of Viral Vector Technologies at Heidelberg University in Germany, where he serves as Independent Principal Investigator in the Department of Infectious Diseases, Virology, and Group Leader at the BioQuant Center. His laboratory explores AAV vectors, bocaviruses, viral capsid engineering, gene therapy, CRISPR/Cas, RNAi, and other technologies including high-throughput screening, single-cell RNA sequencing, and machine learning. Dr. Grimm is internationally recognized as a founding pioneer of AAV vector production technology. In 1998, while at the Deutsches Krebsforschungszentrum (German Cancer Research Center), Grimm developed the pDG helper plasmid system—a revolutionary advance that simplified AAV vector production. The traditional AAV production protocol required three plasmids plus helper adenovirus infection. Grimm's pDG system combined AAV rep/cap genes and adenovirus helper functions into a single helper plasmid, creating a helper-virus-free two-plasmid production system that achieved 10-fold higher rAAV titers. The pDG system became the gold standard for AAV vector production worldwide, adopted by thousands of research laboratories and pharmaceutical companies, establishing the foundation for clinical-scale AAV manufacturing. Beyond production technology, Grimm has made seminal contributions to AAV vector safety and design. His 2006 Nature paper with Mark Kay discovered fatal toxicity from high-level shRNA expression in mouse liver due to oversaturation of cellular microRNA pathways through competition for exportin-5. This landmark finding profoundly impacted the RNAi therapy field, prompting re-evaluation of shRNA expression levels and delivery strategies. Grimm's laboratory leads AAV capsid engineering through directed evolution, DNA shuffling, and multispecies cross-breeding approaches. His team developed barcoded AAV capsid screening platforms enabling massively parallel in vivo evaluation of thousands of variants, identifying tissue-specific AAV vectors including myotropic variants. Grimm collaborates with SIRION Biotech and Sanofi to develop next-generation tissue-selective AAV vectors for gene therapies, integrating rational design, directed evolution, and machine learning to optimize AAV properties for clinical applications.

Dirk Grimm哲学博士，是德国海德堡大学病毒载体技术教授，担任感染性疾病病毒学系独立首席研究员和BioQuant中心组长。他的实验室探索AAV载体、博卡病毒、病毒衣壳工程化、基因治疗、CRISPR/Cas、RNAi和其他技术，包括高通量筛选、单细胞RNA测序和机器学习。 Grimm博士国际公认为AAV载体生产技术的奠基先驱。1998年在德国癌症研究中心工作期间，Grimm开发了pDG辅助质粒系统——简化AAV载体生产的革命性进步。传统AAV生产方案需要三个质粒加辅助腺病毒感染。Grimm的pDG系统将AAV rep/cap基因和腺病毒辅助功能合并到单个辅助质粒中，创建了无辅助病毒的双质粒生产系统，达到10倍更高的rAAV滴度。pDG系统成为全球AAV载体生产的金标准，被数千个研究实验室和制药公司采用，为临床规模AAV制造奠定了基础。 除了生产技术，Grimm在AAV载体安全性和设计方面做出了开创性贡献。他2006年与Mark Kay合作的Nature论文发现小鼠肝脏中高水平shRNA表达的致命毒性，这是由于通过竞争exportin-5导致细胞微RNA途径过饱和。这一里程碑发现深刻影响了RNAi治疗领域，促使重新评估shRNA表达水平和递送策略。 Grimm实验室通过定向进化、DNA改组和多物种杂交方法领导AAV衣壳工程化。他的团队开发了条形码AAV衣壳筛选平台，能够大规模并行体内评估数千个变体，识别组织特异性AAV载体，包括肌肉趋向性变体。Grimm与SIRION Biotech和赛诺菲合作开发下一代组织选择性AAV载体用于基因治疗，整合理性设计、定向进化和机器学习以优化AAV特性用于临床应用。