Combination therapy with losartan and RTA-408 in a recessive dystrophic epidermolysis bullosa (RDEB) mouse model

Summary: Recessive Dystrophic Epidermolysis Bullosa (RDEB) is a severe skin disorder caused by COL7A1 mutations, leading to chronic skin fragility, fibrosis, and inflammation. This study explores the therapeutic potential of combining Losartan, an angiotensin II receptor antagonist with previously described antifibrotic properties, and RTA-408 (omaveloxolone), a powerful Nrf2 activator that helps reduce oxidative stress in cells with previously described efficacy in a murine model of junctional epidermolysis bullosa. To optimize treatment strategies, we tested the effects of single and dual-drug therapies on symptom severity in hypomorphic collagen VII mice. Five-week-old mice were treated with either Losartan (0.6 g/L in drinking water), RTA-408 (3% in corn oil, applied topically), corn oil control, or combination therapy with both Losartan and RTA-408. Treatments were administered for four weeks, followed by a four-week observation period. Anatomical evaluation revealed no consistent benefits in fibrosis, ear folding, or paw digit loss with combination therapy when compared with controls. However, immune cell infiltration analysis of ear skin showed a notable increase in CD45 expression with monotherapy for RTA-408 treated animals (68% increase, P-Value 0.0204), whereas combination therapy mitigated this response, suggesting a possible modulation of the immune response with losartan treatment. Our findings indicate that the combination of Losartan and RTA-408 had limited therapeutic benefits compared with single-drug treatment. These results support the continued exploration of multi-drug approaches to mitigate fibrosis and inflammation in RDEB and related disorders. Sarah M. Halawani¹, Grace Tartaglia², Brenda Solomon², Micheal Alexander², Pyung Hun Park², Andrew P. South¹ 1. Dermatology, University of Wisconsin System, Madison, WI, United States. 2. Dermatology and Cutaneous Biology, and Pharmacology, Physiology and Cancer Biology,, Thomas Jefferson University, Philadelphia, PA, United States. Genetic Disease, Gene Regulation, Gene Therapy & Epigenetics