Chemical modifications of adenine base editor mRNA and guide RNA expand its application scope

Jiang, Tingting; Henderson, Jordana M.; Coote, Kevin; Cheng, Yi; Valley, H.; Zhang, Xiao‐Ou; Wang, Qin; Rhym, Luke H.; Cao, Yusong; Newby, Gregory A.; Bihler, Hermann; Mense, Martin; Weng, Zhiping; Anderson, Daniel G.; McCaffrey, Anton P.; Liu, David R.; Xue, Wen

doi:10.1038/s41467-020-15892-8

Cited by 80 publications

(68 citation statements)

References 36 publications

(61 reference statements)

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“…Without a double-strand DNA break, base editing can lead to single nucleotide conversion and therefore can be used as a reliable tool for genome editing and potentially correct the disease-related mutations in the genome ( 16 ). In vivo mRNA delivery of base editors using lipid nanoparticles (LNPs) has attracted great interest ( 19 , 20 ), whereas most of the current studies used viral vectors for in vivo base editing or direct gene engineering on zygotes ( 16 , 21 ).…”

Section: Introductionmentioning

confidence: 99%

Functionalized lipid-like nanoparticles for in vivo mRNA delivery and base editing

et al. 2020

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Messenger RNA (mRNA) therapeutics have been explored to treat various genetic disorders. Lipid-derived nanomaterials are currently one of the most promising biomaterials that mediate effective mRNA delivery. However, efficiency and safety of this nanomaterial-based mRNA delivery remains a challenge for clinical applications. Here, we constructed a series of lipid-like nanomaterials (LLNs), named functionalized TT derivatives (FTT), for mRNA-based therapeutic applications in vivo. After screenings on the materials, we identified FTT5 as a lead material for efficient delivery of long mRNAs, such as human factor VIII (hFVIII) mRNA (~4.5 kb) for expression of hFVIII protein in hemophilia A mice. Moreover, FTT5 LLNs demonstrated high percentage of base editing on PCSK9 in vivo at a low dose of base editor mRNA (~5.5 kb) and single guide RNA. Consequently, FTT nanomaterials merit further development for mRNA-based therapy.

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Section: Introductionmentioning

confidence: 99%

Functionalized lipid-like nanoparticles for in vivo mRNA delivery and base editing

et al. 2020

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“…Base editors delivered as chemically modified mRNA were tested in vitro to correct the most common CFTR nonsense mutation, W1282X. This study obtained efficient reversion of this point mutation and suggests a new method to deliver base editors [79].…”

Section: Correction Of Point Mutation With Base Editorsmentioning

confidence: 99%

Gene Therapy for Cystic Fibrosis: Progress and Challenges of Genome Editing

Maule

Arosio

Cereseto

2020

IJMS

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Since the early days of its conceptualization and application, human gene transfer held the promise of a permanent solution to genetic diseases including cystic fibrosis (CF). This field went through alternated periods of enthusiasm and distrust. The development of refined technologies allowing site specific modification with programmable nucleases highly revived the gene therapy field. CRISPR nucleases and derived technologies tremendously facilitate genome manipulation offering diversified strategies to reverse mutations. Here we discuss the advancement of gene therapy, from therapeutic nucleic acids to genome editing techniques, designed to reverse genetic defects in CF. We provide a roadmap through technologies and strategies tailored to correct different types of mutations in the cystic fibrosis transmembrane regulator (CFTR) gene, and their applications for the development of experimental models valuable for the advancement of CF therapies.

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“…Moreover, due to increased interest in BE, non-viral vectors are under investigation to replace viral constructs as delivery systems [ 21 ]. Jiang et al demonstrated a successful delivery of ABE using lipid nanoparticles in Tyrosinemia I mice, correcting the gene mutation and showing the promise of the BE approach [ 128 ]. Despite the far-reaching capabilities of the BE strategy, a major limitation of this technique has been the ability to generate precise edits beyond the allowed transition mutations.…”

Section: Targets and How To Reach Them: Dna And Rnamentioning

confidence: 99%

Nanomedicine for Gene Delivery and Drug Repurposing in the Treatment of Muscular Dystrophies

et al. 2021

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Muscular Dystrophies (MDs) are a group of rare inherited genetic muscular pathologies encompassing a variety of clinical phenotypes, gene mutations and mechanisms of disease. MDs undergo progressive skeletal muscle degeneration causing severe health problems that lead to poor life quality, disability and premature death. There are no available therapies to counteract the causes of these diseases and conventional treatments are administered only to mitigate symptoms. Recent understanding on the pathogenetic mechanisms allowed the development of novel therapeutic strategies based on gene therapy, genome editing CRISPR/Cas9 and drug repurposing approaches. Despite the therapeutic potential of these treatments, once the actives are administered, their instability, susceptibility to degradation and toxicity limit their applications. In this frame, the design of delivery strategies based on nanomedicines holds great promise for MD treatments. This review focuses on nanomedicine approaches able to encapsulate therapeutic agents such as small chemical molecules and oligonucleotides to target the most common MDs such as Duchenne Muscular Dystrophy and the Myotonic Dystrophies. The challenge related to in vitro and in vivo testing of nanosystems in appropriate animal models is also addressed. Finally, the most promising nanomedicine-based strategies are highlighted and a critical view in future developments of nanomedicine for neuromuscular diseases is provided.

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Chemical modifications of adenine base editor mRNA and guide RNA expand its application scope

Cited by 80 publications

References 36 publications

Functionalized lipid-like nanoparticles for in vivo mRNA delivery and base editing

Functionalized lipid-like nanoparticles for in vivo mRNA delivery and base editing

Gene Therapy for Cystic Fibrosis: Progress and Challenges of Genome Editing

Nanomedicine for Gene Delivery and Drug Repurposing in the Treatment of Muscular Dystrophies

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