Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, USA.
EMBO Mol Med. 2022 Apr 7;14(4):e14297. doi: 10.15252/emmm.202114297. Epub 2022 Mar 17.
T cells are the current choice for many cell therapy applications. They are relatively easy to access, expand in culture, and genetically modify. Rapamycin-conditioning ex vivo reprograms T cells, increasing their memory properties and capacity for survival, while reducing inflammatory potential and the amount of preparative conditioning required for engraftment. Rapamycin-conditioned T cells have been tested in patients and deemed to be safe to administer in numerous settings, with reduced occurrence of infusion-related adverse events. We demonstrate that ex vivo lentivirus-modified, rapamycin-conditioned CD4 T cells can also act as next-generation cellular delivery vehicles-that is, "micropharmacies"-to disseminate corrective enzymes for multiple lysosomal storage disorders. We evaluated the therapeutic potential of this treatment platform for Fabry, Gaucher, Farber, and Pompe diseases in vitro and in vivo. For example, such micropharmacies expressing α-galactosidase A for treatment of Fabry disease were transplanted in mice where they provided functional enzyme in key affected tissues such as kidney and heart, facilitating clearance of pathogenic substrate after a single administration.
T 细胞是目前许多细胞治疗应用的首选。它们相对容易获取、在培养中扩增，并且可以进行基因修饰。雷帕霉素处理可在体外重新编程 T 细胞，增加其记忆特性和存活能力，同时降低炎症潜力和移植所需的预处理条件。雷帕霉素处理的 T 细胞已在患者中进行了测试，被认为在许多情况下是安全的，可以使用，输注相关不良反应的发生率降低。我们证明，体外慢病毒修饰、雷帕霉素处理的 CD4 T 细胞也可以作为下一代细胞递药载体，即“微型药房”，来传播多种溶酶体贮积症的校正酶。我们在体外和体内评估了这种治疗平台用于 Fabry、Gaucher、Farber 和 Pompe 病的治疗潜力。例如，表达 α-半乳糖苷酶 A 用于治疗 Fabry 病的这种微型药房，在接受治疗的小鼠中移植后，可以在肾脏和心脏等关键受累组织中提供功能性酶，在单次给药后促进致病底物的清除。
