122 - Beyond Proof of Concept, Interventional Gene Therapy: Successful Transduction of Pancreatic Islet Cells in Non-Human Primates by Wedged Retrograde Pancreatic Duct Injection Using Adeno-Associated Virus Vectors

Purpose: To establish a translational interventional gene therapy platform using Adeno-Associated Virus Vectors in non-human primates for type 1 diabetes (T1D).

Materials and Methods: 14 rhesus macaques (1.1–5.4 yrs, mean 3.1; wt 2.3–10.8 kg, mean 4.6) underwent mini-laparotomy with duodenotomy under general anesthesia. The major duodenal papilla was surgically exposed and cannulated using a 24-gauge angiocath. Pancreatic duct injection was performed with iodinated contrast, followed by insertion of a 0.010-inch guidewire to facilitate placement of either a 4–5 Fr micropuncture outer sheath or a 7 Fr sheath introducer. After confirming wedged positioning, various AAV vectors were infused into the pancreatic ductal with a 20-minute dwell. Serum amylase, lipase, and vector levels were measured before and after infusion. Animals were maintained for a 3–6 wk incubation period prior to tissue harvest for histopathologic analysis.

Results: Technical procedural success was achieved in all 14 cases (100%). Wedged retrograde injection enabled reliable delivery of AAV vectors into the pancreatic parenchyma (mean injected dose 8.9×10^12 vg) at the pancreatic body. All animals demonstrated transient, asymptomatic elevations in serum amylase and lipase between 4–24 hours post-injection, returning to baseline thereafter. Histological evaluation confirmed successful transduction of pancreatic acinar and islet cells in all animals, with clear variability in transduction efficiency and islet cell selectivity among vector subtypes. Of particular note, the AAV-KP1 vector exhibited high tropism for islet cells and minimal off-target organ transduction, suggesting vector-dependent optimization for targeted therapy.

Conclusion: This study demonstrates that interventional gene therapy has moved beyond theoretical application. Wedged retrograde pancreatic duct injection of AAV vectors enables safe and efficient transduction of pancreatic islet cells in NHPs. The vector-specific findings, particularly with AAV-KP1, highlight the feasibility of achieving islet-selective gene delivery, establishing a promising translational platform for future clinical applications in T1D.