Pancreas-directed AAV8 -hSPINK1 gene therapy safely and effectively protects against pancreatitis in mice.

Autor:	Wang YC; Department of Gastroenterology, Changhai Hospital, Naval Medical University, Shanghai, China.; Shanghai Institute of Pancreatic Diseases, Shanghai, China.; National Key Laboratory of Immunity and Inflammation, Naval Medical University, Shanghai, China.; Shanghai Key Laboratory of Nautical Medicine and Translation of Drugs and Medical Devices, Shanghai, China., Mao XT; Department of Gastroenterology, Changhai Hospital, Naval Medical University, Shanghai, China.; Shanghai Institute of Pancreatic Diseases, Shanghai, China., Sun C; Department of Gastroenterology, Changhai Hospital, Naval Medical University, Shanghai, China., Wang YH; Department of Gastroenterology, Changhai Hospital, Naval Medical University, Shanghai, China.; Shanghai Institute of Pancreatic Diseases, Shanghai, China., Zheng YZ; Department of Gastroenterology, Changhai Hospital, Naval Medical University, Shanghai, China.; Shanghai Institute of Pancreatic Diseases, Shanghai, China., Xiong SH; Department of Gastroenterology, Changhai Hospital, Naval Medical University, Shanghai, China.; Shanghai Institute of Pancreatic Diseases, Shanghai, China., Liu MY; Department of Gastroenterology, No. 905 Hospital of PLA Navy Affiliated to Naval Medical University, Shanghai, China., Mao SH; Department of Gastroenterology, Changhai Hospital, Naval Medical University, Shanghai, China.; Shanghai Institute of Pancreatic Diseases, Shanghai, China., Wang QW; Department of Gastroenterology, Changhai Hospital, Naval Medical University, Shanghai, China.; Shanghai Institute of Pancreatic Diseases, Shanghai, China., Ma GX; Department of Gastroenterology, Changhai Hospital, Naval Medical University, Shanghai, China.; Shanghai Institute of Pancreatic Diseases, Shanghai, China., Wu D; Department of Gastroenterology, Changhai Hospital, Naval Medical University, Shanghai, China.; Shanghai Institute of Pancreatic Diseases, Shanghai, China., Li ZS; Department of Gastroenterology, Changhai Hospital, Naval Medical University, Shanghai, China.; Shanghai Institute of Pancreatic Diseases, Shanghai, China.; National Key Laboratory of Immunity and Inflammation, Naval Medical University, Shanghai, China.; Shanghai Key Laboratory of Nautical Medicine and Translation of Drugs and Medical Devices, Shanghai, China., Chen JM; Univ Brest, Inserm, EFS, UMR 1078, GGB, Brest, France., Zou WB; Department of Gastroenterology, Changhai Hospital, Naval Medical University, Shanghai, China liaozhuan@smmu.edu.cn dr.wenbinzou@hotmail.com.; Shanghai Institute of Pancreatic Diseases, Shanghai, China.; National Key Laboratory of Immunity and Inflammation, Naval Medical University, Shanghai, China.; Shanghai Key Laboratory of Nautical Medicine and Translation of Drugs and Medical Devices, Shanghai, China., Liao Z; Department of Gastroenterology, Changhai Hospital, Naval Medical University, Shanghai, China liaozhuan@smmu.edu.cn dr.wenbinzou@hotmail.com.; Shanghai Institute of Pancreatic Diseases, Shanghai, China.; National Key Laboratory of Immunity and Inflammation, Naval Medical University, Shanghai, China.; Shanghai Key Laboratory of Nautical Medicine and Translation of Drugs and Medical Devices, Shanghai, China.
Jazyk:	angličtina
Zdroj:	Gut [Gut] 2024 Jun 06; Vol. 73 (7), pp. 1142-1155. Date of Electronic Publication: 2024 Jun 06.
DOI:	10.1136/gutjnl-2023-330788
Abstrakt:	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 2×10 11 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. Competing Interests: Competing interests: None declared. (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)
Databáze:	MEDLINE
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