Develop a Compact RNA Base Editor by Fusing ADAR with Engineered EcCas6e.

Adv Sci (Weinh)

HuidaGene Therapeutics Co. Ltd., 6th Floor, Unit 3, Building 5, No. 160 Basheng Road, Pudong New Area, Shanghai, 200131, China.

Published: June 2023

AI Article Synopsis

  • Researchers developed a new RNA base editor called compact and efficient RNA base editor (ceRBE) that replaces the larger dCas13 protein, improving its in vivo application capabilities.
  • The ceRBE efficiently edits adenine-to-inosine (A-to-I) and cytidine-to-uridine (C-to-U) while minimizing off-target effects in HEK293T cells.
  • In a humanized mouse model for Duchenne muscular dystrophy, ceRBE successfully repaired a mutation and restored gene expression, indicating its potential for treating genetic diseases.

Article Abstract

Catalytically inactive CRISPR-Cas13 (dCas13)-based base editors can achieve the conversion of adenine-to-inosine (A-to-I) or cytidine-to-uridine (C-to-U) at the RNA level, however, the large size of dCas13 protein limits its in vivo applications. Here, a compact and efficient RNA base editor (ceRBE) is reported with high in vivo editing efficiency. The larger dCas13 protein is replaced with a 199-amino acid EcCas6e protein, derived from the Class 1 CRISPR family involved in pre-crRNA processing, and conducted optimization for toxicity and editing efficiency. The ceRBE efficiently achieves both A-to-I and C-to-U base editing with low transcriptome off-target in HEK293T cells. The efficient repair of the DMD Q1392X mutation (68.3±10.1%) is also demonstrated in a humanized mouse model of Duchenne muscular dystrophy (DMD) after AAV delivery, achieving restoration of expression for gene products. The study supports that the compact and efficient ceRBE has great potential for treating genetic diseases.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10265090PMC
http://dx.doi.org/10.1002/advs.202206813DOI Listing

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