Integrated Technology Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
Integrated Technology Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
J Control Release. 2016 Sep 10;237:1-13. doi: 10.1016/j.jconrel.2016.06.036. Epub 2016 Jun 29.
Despite considerable efforts to develop efficient carriers, the major target organ of short-interfering RNAs (siRNAs) remains limited to the liver. Expanding the application outside the liver is required to increase the value of siRNAs. Here we report on a novel platform targeted to muscular organs by conjugation of siRNAs with anti-CD71 Fab' fragment. This conjugate showed durable gene-silencing in the heart and skeletal muscle for one month after intravenous administration in normal mice. In particular, 1μg siRNA conjugate showed significant gene-silencing in the gastrocnemius when injected intramuscularly. In a mouse model of peripheral artery disease, the treatment with myostatin-targeting siRNA conjugate by intramuscular injection resulted in significant silencing of myostatin and hypertrophy of the gastrocnemius, which was translated into the recovery of running performance. These data demonstrate the utility of antibody conjugation for siRNA delivery and the therapeutic potential for muscular diseases.
尽管人们付出了相当大的努力来开发有效的载体，但短干扰 RNA（siRNA）的主要靶器官仍然仅限于肝脏。为了提高 siRNA 的价值，需要将其应用扩展到肝脏以外的部位。在这里，我们报告了一种通过将 siRNA 与抗 CD71 Fab'片段缀合来靶向肌肉器官的新型平台。该缀合物在正常小鼠静脉给药后一个月内可在心脏和骨骼肌中持续进行基因沉默。特别是，当肌内注射时，1μg siRNA 缀合物在比目鱼肌中显示出显著的基因沉默。在周围动脉疾病的小鼠模型中，肌内注射肌肉生长抑制素靶向 siRNA 缀合物的治疗导致肌肉生长抑制素的显著沉默和比目鱼肌的肥大，这转化为跑步性能的恢复。这些数据证明了抗体缀合用于 siRNA 递送的实用性和肌肉疾病的治疗潜力。
