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Pancreas-directed AAV8-hSPINK1 gene therapy safely and effectively protects against pancreatitis in mice
Yuan-Chen Wang1,2,3,4, Xiao-Tong Mao1,2, Chang Sun1
1Department of Gastroenterology, Changhai Hospital, Naval Medical University, Shanghai, China.
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.
Insights
Gene therapy using AAV8-hSPINK1 shows promise for treating chronic pancreatitis (CP). A single injection safely targets the pancreas, reducing disease severity and promoting recovery in mouse models.
Area of Science:
- Gastroenterology
- Gene Therapy
- Pancreatic Diseases
Background:
- Chronic pancreatitis (CP) lacks a cure, with SPINK1 gene variants linked to disease progression.
- Current treatments focus on symptom management rather than addressing underlying causes.
Purpose of the Study:
- To investigate the therapeutic potential of adeno-associated virus type 8 (AAV8)-mediated human SPINK1 (hSPINK1) gene therapy for CP.
- To evaluate the safety and efficacy of AAV8-hSPINK1 in preclinical mouse models of pancreatitis.
Main Methods:
- Construction of a capsid-optimized AAV8 vector for hSPINK1 expression targeting the pancreas.
- Administration of AAV8-hSPINK1 via intraperitoneal injection in mice.
- Assessment of pancreatic transduction efficiency, safety, and therapeutic effects in three distinct pancreatitis mouse models.
Main Results:
- AAV8-hSPINK1 demonstrated specific and safe pancreatic targeting with high transduction efficiency and low off-target organ tropism.
- A single dose of AAV8-hSPINK1 significantly alleviated pancreatitis severity, reduced fibrosis and apoptosis, and accelerated recovery in all tested models.
- Therapeutic effects were observed up to at least 8 weeks post-injection.
Conclusions:
- AAV8-hSPINK1 gene therapy offers a safe and effective approach for pancreatitis prevention and treatment.
- This preclinical study highlights a promising new avenue for managing chronic pancreatitis.
