文献类型：期刊文献

英文题名：Sildenafil increases AAV9 transduction after a systemic administration and enhances AAV9-dystrophin therapeutic effect in mdx mice

作者：Zhou, Kaiyi[1];Yuan, Meng[1];Sun, Jiabao[1];Zhang, Feixu[2];Zong, Xiaoying[1];Li, Zhanao[1];Tang, Dingyue[2];Zhou, Lichen[3];Zheng, Jing[4];Xiao, Xiao[1,5];Wu, Xia[1]

机构：[1]East China Univ Sci & Technol, Sch Pharm, Shanghai, Peoples R China;[2]East China Univ Sci & Technol, Sch Biotechnol, State Key Lab Bioreactor Engn, Shanghai, Peoples R China;[3]Gen Hosp Western Theater Command PLA, Luzhou, Sichuan, Angola;[4]Belief BioMed, Shanghai, Peoples R China;[5]Univ N Carolina, Eshelman Sch Pharm, Div Pharmacoengn & Mol Pharmaceut, Chapel Hill, NC 27517 USA

年份：2024

卷号：31

期号：1-2

起止页码：19

外文期刊名：GENE THERAPY

收录：;WOS:【SCI-EXPANDED(收录号:WOS:001034418400001)】；

语种：英文

摘要：Adeno-associated virus (AAV) vectors have been successfully used to deliver genes for treating rare diseases. However, the systemic administration of high AAV vector doses triggers several adverse effects, including immune response, the asymptomatic elevation of liver transaminase levels, and complement activation. Thus, improving AAV transduction and reducing AAV dosage for treatment is necessary. Recently, we found that a phosphodiesterase-5 inhibitor significantly promoted AAV9 transduction in vitro by regulating the caveolae and macropinocytosis pathways. When AAV9-Gaussian luciferase (AAV9-Gluc) and AAV9-green fluorescent protein (AAV9-GFP) were injected intravenously into mice pre-treated with sildenafil, the expressions of Gluc in the plasma and GFP in muscle tissues significantly increased (P < 0.05). Sildenafil also improved Evans blue permeation in tissues. Additionally, we found that sildenafil promoted Treg proliferation, inhibited B-cell activation, and decreased anti-AAV9 IgG levels (P < 0.05). Furthermore, sildenafil significantly promoted Duchenne muscular dystrophy gene therapy efficacy using AAV9 in mdx mice; it increased micro-dystrophin gene expression, forelimb grip strength, and time spent on the rotarod test, decreased serum creatine kinase levels, and ameliorated histopathology by improving muscle cell morphology and reducing fibrosis (P < 0.05). These results show that sildenafil significantly improved AAV transduction, suppressed the levels of anti-AAV9 IgG, and enhanced the efficacy of gene therapy.