Swine reporter model for preclinical evaluation and characterization of gene delivery vectors

Delivery of gene therapy vectors efficiently targeted to any somatic cell remains a key barrier for the development of genetic medicines. While rodent models provide insights into vector biodistribution and cellular tropism, their anatomical and physiological differences from humans limit their translational potential and studies in large animal models are often required. In this study, we developed a swine reporter model (SRM-1) to evaluate both viral and non-viral vector delivery in a large animal system. The SRM-1 model harbors a tdTomato reporter at the ROSA26 locus that can be activated by Cre recombinase or CRISPR-Cas reagents and allows for tracking of gene delivery vectors in vivo. To evaluate this model, we administered adeno-associated virus serotype 9 (AAV9) and lipid nanoparticles (LNPs) carrying messenger RNA (mRNA) systemically and found successful in vivo reporter activation across a variety of tissues. Intracerebroventricular (i.c.v.) administration of LNP-mRNA was also performed and demonstrated localized activation in cortical brain cells. In addition to systemic biodistribution studies, this model has utility for testing clinically relevant local administration methods, surgical and non-surgical, of delivery vectors. Our findings support the SRM-1 model as a valuable tool for advancing gene therapies from preclinical testing to clinical application.