Perrelli Andrea, Bozza Annalisa, Ferraris Chiara, Osella Sara, Moglia Andrea, Mioletti Silvia, Battaglia Luigi, Retta Saverio Francesco
Department of Clinical and Biological Sciences, University of Torino, 10043 Orbassano, TO, Italy.
CCM Italia Research Network, National Coordination Center at the Department of Clinical and Biological Sciences, University of Torino, 10043 Orbassano, TO, Italy.
Biomedicines. 2023 Feb 7;11(2):480. doi: 10.3390/biomedicines11020480.
Cerebral cavernous malformation (CCM) or cavernoma is a major vascular disease of genetic origin, whose main phenotypes occur in the central nervous system, and is currently devoid of pharmacological therapeutic strategies. Cavernomas can remain asymptomatic during a lifetime or manifest with a wide range of symptoms, including recurrent headaches, seizures, strokes, and intracerebral hemorrhages. Loss-of-function mutations in are responsible for more than 50% of all familial cases, and have been clearly shown to affect cellular junctions, redox homeostasis, inflammatory responses, and angiogenesis. In this study, we investigated the therapeutic effects of multidrug-loaded lipid nanoemulsions in rescuing the pathological phenotype of CCM disease. The pro-autophagic rapamycin, antioxidant avenanthramide, and antiangiogenic bevacizumab were loaded into nanoemulsions, with the aim of reducing the major molecular dysfunctions associated with cavernomas. Through Western blot analysis of biomarkers in an in vitro CCM model, we demonstrated that drug-loaded lipid nanoemulsions rescue antioxidant responses, reactivate autophagy, and reduce the effect of pro-angiogenic factors better than the free drugs. Our results show the importance of developing a combinatorial preventive and therapeutic approach to reduce the risk of lesion formation and inhibit or completely revert the multiple hallmarks that characterize the pathogenesis and progression of cavernomas.
脑海绵状血管畸形（CCM）或海绵状瘤是一种主要的遗传性血管疾病，其主要表型出现在中枢神经系统，目前缺乏药物治疗策略。海绵状瘤在一生中可能无症状，或表现出广泛的症状，包括反复发作的头痛、癫痫、中风和脑出血。超过50%的家族性病例是由功能丧失突变引起的，并且已明确显示这些突变会影响细胞连接、氧化还原稳态、炎症反应和血管生成。在本研究中，我们研究了载有多药的脂质纳米乳剂对挽救CCM疾病病理表型的治疗效果。将促自噬的雷帕霉素、抗氧化剂燕麦酰胺和抗血管生成的贝伐单抗载入纳米乳剂中，目的是减少与海绵状瘤相关的主要分子功能障碍。通过对体外CCM模型中的生物标志物进行蛋白质印迹分析，我们证明载药脂质纳米乳剂比游离药物能更好地挽救抗氧化反应、重新激活自噬并降低促血管生成因子的作用。我们的结果表明，开发一种联合预防和治疗方法以降低病变形成风险并抑制或完全逆转表征海绵状瘤发病机制和进展的多种特征具有重要意义。
