Nature Biotechnology ( IF 33.1 ) Pub Date : 2024-09-13 , DOI: 10.1038/s41587-024-02399-6
Iris Marchal 1
Macromolecular drugs have limited applications in the brain because they cannot cross the blood–brain barrier. A parasite that does have the natural capacity to travel to the brain is Toxoplasma gondii. In a study in Nature Microbiology, Bracha et al. make use of this feature, engineering T. gondii to deliver large proteins to the brains of mice.
The authors targeted several proteins with different sizes, functions and target locations to the protein secretion organelles of T. gondii and tested their delivery to neurons, observing efficient delivery of various therapeutic proteins. The engineered T. gondii could also deliver multiple proteins simultaneously. The authors further characterized their system focusing on the delivery of MeCP2, which is a putative therapeutic target in Rett syndrome. After delivery to brain organoids, MeCP2 bound methylated DNA and altered the expression of known targets, indicating that T. gondii delivered functional MeCP2 protein. The engineered parasite was then used to deliver MeCP2 to the brains of mice. Protein delivery was distributed throughout the brain, with highest levels observed in the cortex.
中文翻译:
工程寄生虫将治疗性蛋白质输送到小鼠大脑
大分子药物在大脑中的应用受到限制,因为它们不能穿过血脑屏障。弓形虫是一种确实具有进入大脑的天然能力的寄生虫。 Bracha 等人在《自然微生物学》的一项研究中。利用这一特性,对弓形虫进行改造,将大蛋白输送到小鼠的大脑中。
作者将几种不同大小、功能和靶位置的蛋白质靶向弓形虫的蛋白质分泌细胞器,并测试了它们向神经元的递送,观察了各种治疗性蛋白质的有效递送。工程改造的弓形虫还可以同时递送多种蛋白质。作者进一步描述了他们的系统,重点关注 MeCP2 的传递,MeCP2 是雷特综合征的假定治疗靶点。在递送至大脑类器官后,MeCP2 结合甲基化 DNA 并改变已知靶标的表达,表明弓形虫递送功能性 MeCP2 蛋白。然后利用改造后的寄生虫将 MeCP2 输送到小鼠的大脑中。蛋白质递送分布在整个大脑中,在皮质中观察到最高水平。