Wang Zhong, Zhu Tong, Qiao Chunping, Zhou Liqiao, Wang Bing, Zhang Jian, Chen Chunlian, Li Juan, Xiao Xiao
Dept. of Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine, 200 Lothrop Street, Pittsburgh, Pennsylvania 15261, USA.
Nat Biotechnol. 2005 Mar;23(3):321-8. doi: 10.1038/nbt1073. Epub 2005 Feb 27.
Systemic gene delivery into muscle has been a major challenge for muscular dystrophy gene therapy, with capillary blood vessels posing the principle barrier and limiting vector dissemination. Previous efforts to deliver genes into multiple muscles have relied on isolated vessel perfusion or pharmacological interventions to enforce broad vector distribution. We compared the efficiency of multiple adeno-associated virus (AAV) vectors after a single injection via intraperitoneal or intravenous routes without additional intervention. We show that AAV8 is the most efficient vector for crossing the blood vessel barrier to attain systemic gene transfer in both skeletal and cardiac muscles of mice and hamsters. Serotypes such as AAV1 and AAV6, which demonstrate robust infection in skeletal muscle cells, were less effective in crossing the blood vessel barrier. Gene expression persisted in muscle and heart, but diminished in tissues undergoing rapid cell division, such as neonatal liver. This technology should prove useful for muscle-directed systemic gene therapy.
对于肌肉萎缩症的基因治疗而言，将基因全身性递送至肌肉一直是一项重大挑战，其中毛细血管构成了主要障碍并限制了载体的扩散。此前将基因递送至多块肌肉的努力依赖于孤立血管灌注或药物干预来实现广泛的载体分布。我们比较了单次经腹腔或静脉途径注射后多种腺相关病毒（AAV）载体的效率，且未进行额外干预。我们发现，AAV8是穿越血管屏障以在小鼠和仓鼠的骨骼肌及心肌中实现全身性基因转移的最有效载体。诸如AAV1和AAV6等血清型，虽在骨骼肌细胞中表现出强大的感染能力，但在穿越血管屏障方面效果较差。基因表达在肌肉和心脏中持续存在，但在经历快速细胞分裂的组织（如新生肝脏）中则有所减少。这项技术应会被证明对肌肉定向全身性基因治疗有用。
