Genprex : ASGCT 2026 Poster - Pancreatic Delivery of AAV-Pdx1/MafA Reverses Hyperglycemia in a Preclinical Model of Type 2 Diabetes
GNPX
Published on 05/13/2026 at 09:49 pm EDT
Introduction
Type 2 diabetes (T2D) is a major public-health and economic burden with no current cure, affecting millions of people in the U.S.
T2D is characterized by insulin resistance, early β-cell dysfunction, and then progressive loss of β-cell mass.
In humans with T2D, chronic hyperglycemia and dyslipidemia reduce key β-cell transcription factors such as PDX1 and MAFA, contributing to loss of β-cell identity and impaired function.1
Methods
Eight-week-old male C57BL/6 mice were maintained on regular diet (RD) or high-fat diet (HFD) for 24 weeks. HFD mice then underwent intrapancreatic infusion of AAV-8 encoding Pdx1 and MafA (PM) under either the CMV promoter (global islet targeting) or rat insulin promoter (RIP; β-cell-specific targeting), received a control virus, or remained unoperated. The viral dose used was 1 × 10^11 viral genomes (vg).
At 4 weeks after surgery, metabolic testing included IPGTT, ITT, GSIS, and glucagon secretion assessment were performed.
Mice were then euthanized for pancreatic histology, quantification of β- and α-cell mass, electron microscopy (EM), and islets were isolated for ex-vivo GSIS and single-cell RNA sequencing.
Results
A • Transcriptomic pseudotime analysis demonstrated a shift
in β-cells from an immature state toward a more mature state after PM treatment.
Trajectory analysis demonstrated enrichment of Cluster 1, characterized by increased expression of β-cell maturation markers such as (Ins1, Ins2, Nkx6.1, Iapp, Ucn3) in PM-treated HFD mice. In contrast, Cluster 0, which showed increased Gcg expression and reduced expression of β-cell maturation markers, was more prevalent in HFD mice treated with control virus.
B C
D test (IPGTT; n = 7-8/group). (A) Right panel, Area under
At 4 weeks post-surgery, PM-treated HFD mice showed improvement in glucose tolerance, with normalization to RD levels (Fig. 1A). β-cell-specific targeting with RIP similarly reversed hyperglycemia and improved first phase insulin secretion (Fig. 1B). Ex-vivo GSIS showed restoration of insulin secretion in islets from PM-treated HFD mice similar to RD mice (Fig. 1C). During the IPGTT, glucagon was suppressed at 15 and 30 minutes (vs fasting) in RD and PM-treated HFD mice, but not in HFD controls, consistent with improved hyperglucagonemia (Fig. 1.D).
An ITT showed a trend toward improved insulin sensitivity in PM-treated HFD mice, but this group was not significantly different from either HFD controls or RD mice. PM treatment did not alter β-cell mass compared with HFD controls but significantly reduced α-cell mass.
EM imaging demonstrated that PM-treated HFD mice had increased numbers of total insulin granules compared with HFD controls (Fig. 2). In contrast, β-cells from HFD control mice exhibited increased numbers of non-insulin granules compared with PM-treated HFD mice. Mitochondrial morphology was also improved in PM-treated HFD mice relative to HFD controls (Fig. 2).
the curve (AUC) analysis of the IPGTT. (B) Early-phase insulin secretion during IPGTT (n = 3-4/group). (C) Ex-vivo glucose-stimulated insulin secretion (GSIS) in isolated islets (n = 5-6/group; 30 islets/mouse). (D) Glucagon measurment during IPGTT (n = 5/group). Data are presented as mean ± SD. Statistical analysis was performed using one-way ANOVA for panels B and D, and two-way ANOVA for panels A and C, followed by Holm-Šídák multiple-comparison testing. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001
A HFD + AAV-PM HFD + AAV-GFP B
Conclusion
PM gene therapy reverses hyperglycemia, likely in large part by specifically enhancing β-cell function and maturation.
This approach is technically translatable to humans via endoscopic retrograde cholangiopancreatography.
References
1. Guo S, Dai C, Guo M, et al. Diabetes. 2013;62:3308-3317
Mohamed Saleh1, Ting Zhang1 , Omar Al Abyad1, Sarah Raad1, Vinitha Dhamotharan1, George Gittes1
1 Division of Pediatric Surgery, Department of Surgery, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
Pancreatic Delivery of AAV-Pdx1/MafA Reverses Hyperglycemia in a Preclinical Model of Type 2 Diabetes
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Genprex Inc. published this content on May 14, 2026, and is solely responsible for the information contained herein. Distributed via Public Technologies (PUBT), unedited and unaltered, on May 14, 2026 at 01:48 UTC.