Boutary Suzan, Khalaf Guy, Landesman Yosef, Madani Mevidette El, Desmaële Didier, Piguet Françoise, Alonso Rafael, Banchi Elena-Gaia, Adams David, Massaad Charbel, Massaad-Massade Liliane
Université Paris-Saclay, Inserm, Maladies et hormones du système nerveux, 94276 Le Kremlin-Bicêtre, France; Université Paris Cité, INSERM UMR_S 1124, 75006 Paris, France.
Université Paris-Saclay, Inserm, Maladies et hormones du système nerveux, 94276 Le Kremlin-Bicêtre, France.
Int J Pharm. 2025 Feb 25;671:125234. doi: 10.1016/j.ijpharm.2025.125234. Epub 2025 Jan 22.
Small interfering RNA (siRNA) has shown promising results for the treatment of Charcot-Marie-Tooth disease 1A (CMT1A) caused by overexpression of peripheral myelin protein (PMP22), leading to myelin dysfunction and axonal damage. Recently, we developed siRNA PMP22-squalene (SQ) nanoparticles (NPs) for intravenous use. Three consecutive injections of siRNA PMP22-SQ NPs at a cumulative dose of 1.5 mg/kg restored motor function in C61 transgenic mouse models. Pharmacokinetic studies showed a long half-life of antisense siRNA PMP22 in the sciatic nerve, and spinal cord, indicating targeted release potential. We further assessed the efficiency and safety of siRNA PMP22-SQ NPs in two healthy male non-human primates (Macaca fascicularis) after administering four escalating doses (0.1, 0.5, 2.5 and 4.5 mg/kg at one week interval). Interestingly, the siRNA PMP22-SQ NPs reduced PMP22 mRNA expression by approximately 70 % and probably induced an early-stage hereditary neuropathy with pressure palsies (HNPP)-like condition in two normal NHP. No preliminary toxicity was observed in organs or blood parameters of the two NHPs. Interestingly, the nerve conduction velocity decreased after the third injection of siRNA PMP22-SQ NPS. These results demonstrate the therapeutic potential of siRNA PMP22-SQ NPs, supporting advancement to further pre-clinical testing.
小分子干扰RNA（siRNA）在治疗由外周髓磷脂蛋白（PMP22）过表达引起的1A型夏科-马里-图斯病（CMT1A）方面已显示出有前景的结果，PMP22过表达会导致髓磷脂功能障碍和轴突损伤。最近，我们开发了用于静脉注射的siRNA PMP22-角鲨烯（SQ）纳米颗粒（NPs）。在C61转基因小鼠模型中，以1.5mg/kg的累积剂量连续三次注射siRNA PMP22-SQ NPs可恢复运动功能。药代动力学研究表明，反义siRNA PMP22在坐骨神经和脊髓中的半衰期很长，表明其具有靶向释放潜力。我们在两只健康雄性食蟹猴（猕猴）中，以四个递增剂量（0.1、0.5、2.5和4.5mg/kg，间隔一周）给药后，进一步评估了siRNA PMP22-SQ NPs的有效性和安全性。有趣的是，siRNA PMP22-SQ NPs使PMP22 mRNA表达降低了约70%，并可能在两只正常食蟹猴中诱发了早期遗传性压力性麻痹神经病（HNPP）样病症。在两只食蟹猴的器官或血液参数中未观察到初步毒性。有趣的是，在第三次注射siRNA PMP22-SQ NPS后，神经传导速度下降。这些结果证明了siRNA PMP22-SQ NPs的治疗潜力，支持推进到进一步的临床前测试。
