I-Corps: Curing inherited diseases at the source through next-generation clustered regularly interspaced short palindromic repeat (CRISPR) systems

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The broader impact/commercial potential of this I-Corps project is the development of technologies that edit genes within living cells. Mutations in critical genes are the underlying cause of many diseases, from cancer to hereditary disorders, and repairing these mutations would significantly improve patients’ quality of life. In addition, performing site-specific modifications at unprecedented precision in the genomes of cells and organisms offers the potential to revolutionize medicine, agriculture, biotechnology, and even basic research practices. Human health has been the subject of most initial studies as, for the first time, gene editing has curative potential in a wide range of debilitating genetic diseases that are currently only addressed via decades of costly treatment. However, current gene editing programs have been focused on a confined set of genetic diseases, primarily driven by delivery challenges with CRISPR-Cas9. Later-stage applications of CRISPR-Cas9 gene editing have been largely ex vivo, with in vivo applications limited to more accessible organ targets (e.g., eye, liver). The proposed technology has the capacity to reach targets that to date have been a challenge to access and potentially cure diseases for which there is significant unmet need.This I-Corps project is based on the development of a genome editing platform that circumvents current in vivo delivery challenges with CRISPR-Cas9. CRISPR/Cas9 requires multiple delivery systems to reach in vivo targets, which may lead to high toxicity and death. The proposed vCas systems consist of miniature RNA-guided genome editors distinct from Cas9, including the world’s most compact and highly efficient CRISPR-Cas systems. At approximately half the size of Cas9, vCas systems provide a template for next-generation genome editing tools that may be easily packaged in safe and existing viral vectors to reach challenging in vivo therapeutic targets. The proposed approach has been validated to generate high editing efficiency in mammalian cells, and the extremely small size of the components compared to existing technologies has the potential to render previously untreatable genetic diseases more accessible.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.