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C2 - Epigenetic Editing and RNA Editing

698: Design and Characterization of Compact and Precise Cas Enzymes for Treating Diseases in Patients

Type: Poster Session

Poster Board Number: 698
Presentation Details
Session Title: Wednesday Posters: Epigenetic Editing and RNA Editing

Genome and epigenome editing each hold immense potential for making targeted, precise corrections to either our genes’ sequences or how they are expressed, clearing new and accelerated paths toward therapies for previously untreatable diseases. However, there remain significant barriers to realizing this potential including the development of genome and epigenome editing tools that are both highly precise and have broad targeting scopes. By combining the precision and broad targeting potential of CRISPR-Cas enzymes with novel regulators of gene expression, Epic Bio’s epigenetic editing platform is at the forefront of gene therapy to mitigate and reverse diseases that are beyond the reach of traditional genome editing.
Our Cas engineering platform has led to the discovery of highly compact nuclease-deficient dCas enzymes, thus enabling efficient delivery by AAV due to their small sizes (one-third the size of SpyCas9), and avoiding double-strand breaks or permanent edits. All clinical applications of Cas-based genome engineering are constrained by the requirements for protospacer-adjacent motifs (PAM) in the target DNA. Importantly, our novel dCas enzymes display flexible PAM requirements and are easily programmed to target therapeutic genes, underlining their broad utility.
Here we present a novel cellular assay for PAM characterization that comprehensively and quantitatively captures the PAM requirements of dCas enzymes in human cells. This assay enables accurate detection of greatly expanded PAM profiles for our lead dCas enzymes (dCasONYX, dCasRUBY, dCasTOPAZ), enabling the efficient targeting of disease-causing genes. This assay enables ongoing engineering and deep characterization of our novel dCas in relevant genomic contexts to facilitate their translation to therapeutics.
Altogether, we present our work to optimize compact and precise Cas molecules at the core of our epigenetic editing platform and demonstrate their broad utility, representing a major advancement toward treating intractable diseases in patients.

Melanie Silvis1, Xiao Yang1, Ryan Swan1, Tabitha Tcheau1, Gabriella Alvarez1, Julia Bachteal1, Chris Still1, Zaki Jawaid1, Vincent Cutillas1, Tengyu Ko1, Blair Gainous1, Brandon Liauw1, Aayushma Gautam1, Stanley Qi1,2,3,4, Tim Daley1, Dan Hart1, Yanxia Liu1

1EpiC-BIO, South San Francisco, CA,2Department of Bioengineering, Stanford University, Stanford, CA,3ChEM-H, Stanford University, Stanford, CA,4Chan Zuckerberg Biohub, San Francisco, CA"

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