Science and Technology Platform Program for Advanced Biological Medicine


Creation of a universal base-editing tool for safe gene therapy

<Project Leader> Osamu Nureki

Professor, Graduate School of Science, The University of Tokyo

Osamu Nureki

Cas9 is widely used as an innovative genome editing tool. However, alarm bells have been sounded about genome editing by “cutting” because genomic cleavage can cause gene deletion. In response, there has been increasing interest in base-editing tools that combine Cas9 stripped of its DNA-cleaving activity by using deaminated enzymes as a type of genome editing technology that does not require cutting. Base-editing technology promises to be particularly useful in gene therapy because many congenital genetic disorders are caused by point mutations. However, only limited areas of the genome are targetable with base-editing technology because a specific base sequence is required for Cas9 to recognize the target DNA. In addition, a base-editing tool small enough to be incorporated into a viral vector must be developed to enable in vivo base editing. The aim of this research project is to develop a universal base-editing toolset with expanded utility through analysis of the structure and function of smaller versions of Cas9 and Cas12 and molecular modification. The performance of the developed base-editing tool will be evaluated in iPS cell and mouse models of congenital hemophilia as a model congenital disorder. This plan will be used to create treatment strategies for genetic disorders targeting various mutations.

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