Active Genetic Neutralizing Elements for Halting or Deleting Gene Drives.

Abstract

CRISPR-Cas9-based gene drive systems possess the inherent capacity to spread progressively throughout target populations. Here we describe two self-copying (or active) guide RNA-only genetic elements, called e-CHACRs and ERACRs. These elements use Cas9 produced in trans by a gene drive either to inactivate the cas9 transgene (e-CHACRs) or to delete and replace the gene drive (ERACRs). e-CHACRs can be inserted at various genomic locations and carry two or more gRNAs, the first copying the e-CHACR and the second mutating and inactivating the cas9 transgene. Alternatively, ERACRs are inserted at the same genomic location as a gene drive, carrying two gRNAs that cut on either side of the gene drive to excise it. e-CHACRs efficiently inactivate Cas9 and can drive to completion in cage experiments. Similarly, ERACRs, particularly those carrying a recoded cDNA-restoring endogenous gene activity, can drive reliably to fully replace a gene drive. We compare the strengths of these two systems.

Evidence profile

Study type

laboratory

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Abstract only

Publication status

published

Corrections or retractions

none

Conflict statement

Declaration of Interests E.B., V.M.G., and O.S.A. have equity interest in Synbal Inc. (E.B. and V.M.G.) and Agragene (E.B., V.G., and O.S.A.). These companies may potentially benefit from the research results. E.B. and V.M.G. also serve on the Board of Directors and Scientific Advisory Board for Synbal Inc., and E.B., V.M.G., and O.S.A. serve on the Scientific Advisory Board for Agragene Inc. The terms of these arrangements have been reviewed and approved by the University of California, San Diego, in accordance with its conflict-of-interest policies. All other authors declare no competing interests.

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