Development of a Nonviral Genetic Medicine for ADPKD Administered through Targeted Transcutaneous Ultrasound-Mediated Delivery

Background: Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the formation and growth of fluid-filled renal cysts, often leading to kidney failure. The most frequent genetic cause of ADPKD are monogenic mutations in the PKD1 gene. Ultrasound mediated gene delivery (UMGD) is an effective approach for noninvasive targeted transgene delivery into renal cells, enabling the development of a nonviral gene replacement therapy for ADPKD. Methods: Using genetic engineering and screening of next generation DNA payload formats, we developed an optimized DNA construct expressing a full-size PKD1 protein. Transgenic PKD1 expression was assessed in vitro in relevant renal cells. To evaluate the potential of UMGD as a nonviral ADPKD treatment option, we delivered genetic constructs to the cystic kidney of an ADPKD mouse model using proprietary acoustic energy profiles and FDA-approved ultrasound components. Results: Testing multiple variants of codon-optimized full-size PKD1 open reading frame sequences along with proximal tubular epithelial cells-specific promoter enabled robust transgenic PKD1 protein expression in ADPKD cystic cells. SonoThera’s highly optimized and proprietary acoustic energy profiles has enabled the targeted delivery of optimized genetic constructs to the cells of cystic kidneys of an ADPKD mouse model. Conclusion: High levels of tissue-specific transgenic full-length PKD1 expression along with the favorable efficacy and safety profile of ultrasound mediated transgene delivery to the cystic cells in ADPKD kidney supports further translation of this approach into clinical development for the treatment of ADPKD.