Kidney-Targeted Delivery of Nonviral Nucleic Acids Using Noninvasive Transcutaneous Ultrasound Enables Safe, Re-dosable, Titratable, and Durable Gene Expression in Mice and Nonhuman Primates

Background: Effective kidney-targeted delivery of genetic medicines has been elusive despite significant research. Transcutaneous ultrasound-mediated gene delivery (UMGD) offers a noninvasive, targeted approach to overcome these challenges Methods: SonoThera is developing a proprietary ultrasound-guided nonviral gene therapy platform for selective kidney targeting in a safe, redosable, durable, and titratable manner. In vivo bioluminescence imaging of firefly luciferase reporter gene expression was conducted using an IVIS imaging system at various time points in the kidneys of both wild-type and polycystic kidney disease (Nek8JCK) mouse models. Kidney tissue obtained from mice and nonhuman primates was analyzed for reporter gene presence and expression using ddPCR, RNAscope, snRNA-seq, and immunohistochemistry. Multiple clinical and molecular safety assessments were conducted in mice and nonhuman primates using established methods. Results: SonoThera’s UMGD platform enabled robust, durable, redosable, and titratable transgene expression in wild-type mouse kidneys, with durable gene expression observed for over a year following a single treatment. Renal disease-relevant cell types including podocytes, tubular epithelial cells, and endothelial cells were effectively transfected in mice and nonhuman primates. Robust delivery and transgene expression were confirmed in the polycystic kidney mouse model (Nek8JCK). Safety assessments, including clinical observations, blood urea nitrogen, creatinine levels, and a proinflammatory cytokine panel, indicated excellent tolerability and safety following single and repeat treatments in mice and nonhuman primates. Conclusion: These results provide strong support for the continued development of UMGD for the treatment of renal disease. Funding: Commercial Support - Sonothera Inc.