Chemical and lipid nanoparticle-siRNA inhibition of GLUT1 rescues in vivo models of psoriasis

Summary: Abstract Body: GLUT1 is critical for energy generation, redox homeostasis, and lipid synthesis in vitro, but GLUT1-mediated glucose transport is dispensable for normal skin development and barrier function in vivo. Because GLUT1 is highly overexpressed in the lesional skin of psoriasis patients, we tested whether it could be inhibited as a novel approach for psoriasis. Previously, we found that mice with an epidermal deletion of GLUT1 were dramatically rescued from mouse models of psoriasiform hyperplasia. To advance the specific targeting of GLUT1 for patients, we tested two novel approaches of inhibiting the GLUT1 transporter in vivo. First, novel Selective Organ Targeting (SORT) lipid nanoparticle were formulated and tested for their ability to deliver RNA to skin. Efficient SORT-LNPs were selected and used to deliver siRNAs targeting Slc2a1 (GLUT1) to mouse skin. A single injection of LNP-siGlut1 significantly inhibited GLUT1 RNA and protein expression and significantly rescued imiquimod-mediated psoriasiform dermatitis in mice. In parallel, our prior work demonstrated that small molecule inhibitors of GLUT1 could also ameliorate psoriasis models in vivo. Here, we focused on the small molecule phloretin due to its availability as topical cosmeceutical products. Phloretin potently inhibited 2-deoxyglucose transport in vitro and improved markers of psoriasiform hyperplasia in skin organoid models. Daily application of phloretin also significantly rescued imiquimod mediated psoriasiform dermatitis in mice. Our findings offer novel, feasible approaches to treat psoriasis. More broadly, our studies advance LNP-siRNA and phloretin as novel therapeutic approaches for a broad range of genetic and inflammatory skin diseases. Dapeng Yun¹, Amogh Vaidya², Jiawei Zhao³, Lukas Farbiak², Daniel Siegwart², Richard Wang¹ 1. Dermatology, The University of Texas Southwestern Medical Center, Dallas, TX, United States. 2. Biomedical Engineering, The University of Texas Southwestern Medical Center, Dallas, TX, United States. 3. Shenzhen University of Advanced Technology, Shenzhen, Guangdong, China. Genetic Disease, Gene Regulation, Gene Therapy & Epigenetics