Background: The coexistence of interrelated metabolic diseases, such as obesity and metabolic dysfunction-associated steatotic liver disease (MASLD, formerly known as non-alcoholic fatty liver disease [NAFLD]), has risen dramatically, attributed to the overnutrition and sedentary lifestyle of modern society. Despite the clinical effectiveness of glucagon-like peptide 1 (GLP-1)-based therapies, durability of effect remains challenging as most patients regain weight upon treatment discontinuation. We have developed a novel, adeno-associated virus, gene therapy platform enabling durable production of proteins, including GLP-1-based therapies, by the pancreas. Here, we assessed metabolic efficacy outcomes and durability of a single-dose, GLP-1-based, pancreatic gene therapy (PGTx) compared to daily semaglutide (Sema) in a well-established, murine, diet-induced, obesity and fatty liver model.
Methods: C57BL/6 mice were fed a 60% high-fat diet (HFD) for 25 weeks toward a target body weight (BW) of 50 grams and then randomized into groups: single-dose intraperitoneal (i.p.) PGTx (1e13 vector genomes [VG], n=10), daily subcutaneous (s.c.) Sema (10 nmol/kg/d x 4 weeks, n=10), i.p. PGTx vehicle control (n=8), or daily s.c. Sema vehicle control (n=8) and continued on the HFD post-treatment. Sema was subsequently withdrawn on day 29, and mice were given PGTx (5e12 VG, n=5) or vehicle (n=5) while continuing the HFD. Mean BW and food intake were measured daily over 57 days. Fasting mean terminal liver weight and liver triglycerides were also assessed.
Results: All interventions were well-tolerated throughout the study. On day 28 post-treatment, BW was significantly reduced by 27% with single-dose PGTx vs. 21% with daily Sema (p<0.05). Notably, PGTx-induced BW loss persisted to 57 days post-treatment (p<0.0001) (Figure 1). Sema withdrawal resulted in regain of BW to -2% below baseline, while treatment of Sema-withdrawn animals with PGTx stabilized 28-day BW loss at -22% at day 57 (p<0.001) (Figure 1). Alterations in mean food intake closely mirrored BW changes in all treatment cohorts. Moreover, PGTx significantly reduced mean liver weight and triglyceride content by 42% and 67%, respectively, compared to vehicle control (p<0.01 and p<0.0001) (Figure 2).
Conclusions: Single-dose PGTx can durably reduce BW and also maintain BW reduction upon Sema withdrawal. PGTx-driven BW reductions coincide with improvements in liver weight and hepatic triglycerides. Collectively, these data suggest that PGTx has the potential to advance GLP-1-based therapies toward durable efficacy for metabolic diseases including obesity and MASLD.

Timothy Kieffer

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