SCGE Comparative Studies Supplement

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The Nonhuman Primate Testing Center supports studies that advance the genome editing field, contributing to the future translation of these technologies for the treatment of human disease. The studies proposed in this supplemental application bring together two complementary SCGE Consortium teams to advance combined in vitro and in vivo safety and efficiency testing for somatic cell genome editing. The in vitro component addresses human cells in a 3D organoid model, a rapid and high-throughput testing platform for preclinical assessments. However, the degree to which organoids can predict responses in vivo remains unclear thus this system will be integrated with the synergistic preclinical primate model to address topics of interest to regulatory agencies such as dose response, editing delivery components, safety, and potential toxicities to guide preclinical/clinical monitoring. As a prototype for proof-of-concept, studies focus on the kidney because ~20 million Americans suffer from chronic kidney disease. Kidney disease is on the rise particularly in children, a population that suffers disproportionately from genetic causes that could be targeted with genome editing. CRISPR/Cas9 editing delivered by adeno-associated virus (AAV) is proposed to introduce specific edits at the AAVS1 target locus. This is an ideal candidate because it is expressed in human and rhesus with conserved sequences. In vitro studies in human organoids will be paralleled with investigations that utilize a direct ultrasound guided intrarenal approach in young monkeys. Collectively, these studies will compare human kidney organoids with outcomes in nonhuman primates to establish a new regulatory paradigm which can be applied to a range of tissues and diseases.