Medical Research

City of Hope

Saswati Chatterjee
Duarte, CA
$1,000,000
June 2019

Gene editing is revolutionizing research from medicine to agriculture.  It is enabled by nuclease based platforms, such as CRISPR, which predominantly use error-prone non homologous-end-joining DNA repair, leading to unintended on-target mutations.  Repair of nuclease-induced double stranded DNA breaks via the highly precise homologous recombination (HR) pathway is rare.  Additionally, nuclease-based editing platforms carry the burden of promiscuous off-target cleavage, resulting in the potential for genome-wide mutagenesis.  Thus, significant challenges persist with current editing platforms.  Adeno-associated virus (AAV) based vectors have previously been shown to mediate genome editing without the requirement for exogenous nucleases.  However, genome editing efficiencies were too low to be useful.  Investigators at City of Hope recently reported that AAVHSC, a novel class of human stem cell (HSC)-derived AAV, mediate precise and efficient HR-based genome editing requiring no exogenous nucleases and no genomic scarring.  Genome editing is guided only by homology arms.  However, although this method is effective, little is known about the underlying processes by which any AAV, including AAVHSC, mediate gene editing.  In this project, the team will investigate the mechanisms by which AAVHSC executes this unique, efficient, HR-based editing.  Specifically, they will study the interactions between AAVHSC editing genomes and cellular DNA repair proteins and the role of the AAVHSC capsids in potentiating the efficiency of HR.  Additionally, they will investigate how AAVHSC mediates HR in non-dividing cells.  This study is expected to reveal novel cellular mechanisms that may be harnessed for a range of genomic applications including novel therapies.

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