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Original research
Pancreas-directed AAV8-hSPINK1 gene therapy safely and effectively protects against pancreatitis in mice
  1. Yuan-Chen Wang1,2,3,4,
  2. Xiao-Tong Mao1,2,
  3. Chang Sun1,
  4. Ya-Hui Wang1,2,
  5. Yi-Zhou Zheng1,2,
  6. Si-Huai Xiong1,2,
  7. Mu-Yun Liu5,
  8. Sheng-Han Mao1,2,
  9. Qi-Wen Wang1,2,
  10. Guo-Xiu Ma1,2,
  11. Di Wu1,2,
  12. Zhao-Shen Li1,2,3,4,
  13. Jian-Min Chen6,
  14. Wen-Bin Zou1,2,3,4,
  15. Zhuan Liao1,2,3,4
  1. 1Department of Gastroenterology, Changhai Hospital, Naval Medical University, Shanghai, China
  2. 2Shanghai Institute of Pancreatic Diseases, Shanghai, China
  3. 3National Key Laboratory of Immunity and Inflammation, Naval Medical University, Shanghai, China
  4. 4Shanghai Key Laboratory of Nautical Medicine and Translation of Drugs and Medical Devices, Shanghai, China
  5. 5Department of Gastroenterology, No. 905 Hospital of PLA Navy Affiliated to Naval Medical University, Shanghai, China
  6. 6Univ Brest, Inserm, EFS, UMR 1078, GGB, Brest, France
  1. Correspondence to Professor Zhuan Liao, Department of Gastroenterology, Changhai Hospital, Naval Medical University, Shanghai 200433, China; liaozhuan{at}; Professor Wen-Bin Zou, Department of Gastroenterology, Changhai Hospital, Naval Medical University, Shanghai 200433, China; dr.wenbinzou{at}


Objective Currently, there is no cure for chronic pancreatitis (CP). Germline loss-of-function variants in SPINK1 (encoding trypsin inhibitor) are common in patients with CP and are associated with acute attacks and progression of the disease. This preclinical study was conducted to explore the potential of adeno-associated virus type 8 (AAV8)-mediated overexpression of human SPINK1 (hSPINK1) for pancreatitis therapy in mice.

Design A capsid-optimised AAV8-mediated hSPINK1 expression vector (AAV8-hSPINK1) to target the pancreas was constructed. Mice were treated with AAV8-hSPINK1 by intraperitoneal injection. Pancreatic transduction efficiency and safety of AAV8-hSPINK1 were dynamically evaluated in infected mice. The effectiveness of AAV8-hSPINK1 on pancreatitis prevention and treatment was studied in three mouse models (caerulein-induced pancreatitis, pancreatic duct ligation and Spink1 c.194+2T>C mouse models).

Results The constructed AAV8-hSPINK1 vector specifically and safely targeted the pancreas, had low organ tropism for the heart, lungs, spleen, liver and kidneys and had a high transduction efficiency (the optimal expression dose was 2×1011 vg/animal). The expression and efficacy of hSPINK1 peaked at 4 weeks after injection and remained at significant level for up to at least 8 weeks. In all three mouse models, a single dose of AAV8-hSPINK1 before disease onset significantly alleviated the severity of pancreatitis, reduced the progression of fibrosis, decreased the levels of apoptosis and autophagy in the pancreas and accelerated the pancreatitis recovery process.

Conclusion One-time injection of AAV8-hSPINK1 safely targets the pancreas with high transduction efficiency and effectively ameliorates pancreatitis phenotypes in mice. This approach is promising for the prevention and treatment of CP.


Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information. Not applicable.

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Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information. Not applicable.

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  • Y-CW, X-TM and CS are joint first authors.

  • Contributors Y-CW and X-TM performed the experiments, analysed the data and wrote the manuscript. CS and M-YL provided Spink1 c.194+2T>C mice and contributed to data analysis. Y-HW conducted the RNA sequencing and assisted with data analysis. CS, Y-ZZ, S-HX, S-HM and Q-WW assisted with the construction of animal models. G-XM and DW assisted with data analysis. Z-SL and J-MC contributed to study design and manuscript revision. W-BZ and ZL designed and directed the study and wrote the manuscript. All authors critically revised the manuscript and approved the final manuscript. As the guarantor, ZL is fully responsible for the overall work and the conduct of the study.

  • Funding This study was supported by the National Natural Science Foundation of China (81970560, 82222012, 82120108006), the Scientific Innovation Program of Shanghai Municipal Education Committee (201901070007E00052) and the Research Center Program of Shanghai Municipal Health Commission (2023ZZ02004).

  • Competing interests None declared.

  • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.