132. GW9662 Improves Lymphedema and Mitigates Fibrosis in a Mouse Tail Model

PURPOSE: Lymphedema is a common complication following lymphadenectomy, affecting approximately 5 million people annually in the US. The condition is characterized by lymphatic dysfunction, leading to the accumulation of lymphatic fluid and subsequent fibroadipose tissue deposition in the affected limb. As lymphedema progresses, fibrosis of adipose and soft tissue can lead to irreversible, “end-stage” disease, where traditional treatment options, such as compression therapy, become ineffective. GW9662, a PPARγ antagonist, inhibits adipocyte development and has been shown to attenuate fibrosis in models of non-alcoholic fatty liver disease (NAFLD) and cirrhosis. Here, we aim to investigate whether GW9662 can halt the progression of fibroadipose tissue deposition and fibrosis in a mouse model of lymphedema. METHODS: 6-to-8-week-old mice underwent tail lymphedema surgery. Mice then either received systemic GW9662 (5 mg/kg, n=3) or control (corn oil, n=2) via i.p. injections twice weekly, beginning the week of surgery, or topical GW9662 (5 mg/mL, n=2) or topical control (n=3) applied daily to the tail distal to the surgical site starting the day after surgery. Tail circumference was measured weekly to monitor lymphedema progression. At the end of the study, tails were harvested for histological analysis to assess fibrosis and soft tissue thickness. RESULTS: Systemic administration of GW9662 significantly reduced tail circumference starting at week 2 and throughout the six-week study period compared to control-treated mice (week 2: 1.3cm vs 1.5cm, p=0.017; week 3: 1.3m vs 1.6cm, p=0046; week 4: 1.2cm vs 1.7cm, p=0.045; week 5: 1.1cm vs 1.7cm, p=0.011). In contrast, topical GW9662 did not affect overall tail circumference over a 6-week period but resulted in reduced fibrosis deposition at 6 weeks compared to controls (21.3% vs 37.4%, p<0.001. CONCLUSIONS: This study demonstrates that GW9662 improves lymphedema outcomes in a mouse tail model. Systemic administration significantly reduced tail circumference starting early in treatment compared to control-treated animals. While topical GW9662 did not affect changes in tail circumference, it resulted in significantly decreased fibrosis by the end of the study period. Since fibrosis is a late-stage and often irreversible complication of lymphedema, these findings suggest that GW9662 may serve as a potent therapeutic option for patients at risk for chronic lymphedema. Future studies will focus on optimizing the topical formulation to determine whether higher doses can affect both soft tissue thickness and tail circumference.