PMID- 37500816
OWN - NLM
STAT- MEDLINE
DCOM- 20240116
LR  - 20240116
IS  - 1476-5462 (Electronic)
IS  - 0969-7128 (Linking)
VI  - 31
IP  - 1-2
DP  - 2024 Jan
TI  - Sildenafil increases AAV9 transduction after a systemic administration and 
      enhances AAV9-dystrophin therapeutic effect in mdx mice.
PG  - 19-30
LID - 10.1038/s41434-023-00411-3 [doi]
AB  - 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.
CI  - (c) 2023. The Author(s), under exclusive licence to Springer Nature Limited.
FAU - Zhou, Kaiyi
AU  - Zhou K
AD  - School of Pharmacy, East China University of Science and Technology, Shanghai, 
      China.
FAU - Yuan, Meng
AU  - Yuan M
AD  - School of Pharmacy, East China University of Science and Technology, Shanghai, 
      China.
FAU - Sun, Jiabao
AU  - Sun J
AD  - School of Pharmacy, East China University of Science and Technology, Shanghai, 
      China.
FAU - Zhang, Feixu
AU  - Zhang F
AD  - State Key Laboratory of Bioreactor Engineering, School of Biotechnology, East 
      China University of Science and Technology, Shanghai, China.
FAU - Zong, Xiaoying
AU  - Zong X
AD  - School of Pharmacy, East China University of Science and Technology, Shanghai, 
      China.
FAU - Li, Zhanao
AU  - Li Z
AD  - School of Pharmacy, East China University of Science and Technology, Shanghai, 
      China.
FAU - Tang, Dingyue
AU  - Tang D
AD  - State Key Laboratory of Bioreactor Engineering, School of Biotechnology, East 
      China University of Science and Technology, Shanghai, China.
FAU - Zhou, Lichen
AU  - Zhou L
AD  - The General Hospital of Western Theater Command PLA, Sichuan Province, China.
FAU - Zheng, Jing
AU  - Zheng J
AD  - Belief BioMed, Xuhui District, Shanghai, China.
FAU - Xiao, Xiao
AU  - Xiao X
AD  - School of Pharmacy, East China University of Science and Technology, Shanghai, 
      China. xxiao@email.unc.edu.
AD  - Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of 
      Pharmacy, University of North Carolina, Chapel Hill, NC, 27517, USA. 
      xxiao@email.unc.edu.
FAU - Wu, Xia
AU  - Wu X
AUID- ORCID: 0000-0001-5497-2532
AD  - School of Pharmacy, East China University of Science and Technology, Shanghai, 
      China. wuxia@ecust.edu.cn.
LA  - eng
GR  - 31901052/National Natural Science Foundation of China (National Science 
      Foundation of China)/
GR  - 81970171/National Natural Science Foundation of China (National Science 
      Foundation of China)/
GR  - 20ZR1415000/Shanghai Science and Technology Development Foundation (Shanghai 
      Science and Technology Development Fund)/
GR  - 18SYXHZ0024/Department of Science and Technology of Sichuan Province (Sichuan 
      Provincial Department of Science and Technology)/
PT  - Journal Article
DEP - 20230727
PL  - England
TA  - Gene Ther
JT  - Gene therapy
JID - 9421525
RN  - 0 (Dystrophin)
RN  - BW9B0ZE037 (Sildenafil Citrate)
RN  - 0 (Immunoglobulin G)
SB  - IM
MH  - Mice
MH  - Animals
MH  - *Dystrophin/genetics/metabolism
MH  - Mice, Inbred mdx
MH  - Sildenafil Citrate/pharmacology/therapeutic use/metabolism
MH  - *Muscular Dystrophy, Duchenne/genetics/therapy
MH  - Immunoglobulin G/genetics
MH  - Dependovirus/genetics/metabolism
MH  - Genetic Vectors/genetics
MH  - Muscle, Skeletal/metabolism
EDAT- 2023/07/28 01:08
MHDA- 2024/01/16 06:42
CRDT- 2023/07/27 23:27
PHST- 2022/12/20 00:00 [received]
PHST- 2023/07/17 00:00 [accepted]
PHST- 2023/07/07 00:00 [revised]
PHST- 2024/01/16 06:42 [medline]
PHST- 2023/07/28 01:08 [pubmed]
PHST- 2023/07/27 23:27 [entrez]
AID - 10.1038/s41434-023-00411-3 [pii]
AID - 10.1038/s41434-023-00411-3 [doi]
PST - ppublish
SO  - Gene Ther. 2024 Jan;31(1-2):19-30. doi: 10.1038/s41434-023-00411-3. Epub 2023 Jul 
      27.