CRISPR-Cas9 correction in the DMD mouse model is accompanied by upregulation of Dp71f protein

Егорова, Т. В.; Polikarpova, Anna V.; Vassilieva, Svetlana G.; Dzhenkova, Marina A.; Savchenko, Irina M.; Velyaev, Oleg A.; Shmidt, A. A.; Солдатов, Владислав О.; Pokrovsky, M. V.; Deykin, Alexey V.; Bardina, Maryana V.

doi:10.1016/j.omtm.2023.06.006

Cited by 3 publications

(2 citation statements)

References 74 publications

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“…In a recent study conducted by Tatiana V. Egorova and her colleagues, a new dualcleavage strategy using the CRISPR/Cas9 system was employed to remove exons 6 and 7 of the Dys gene and correct the reading frame of the myotonic dystrophy protein in a DMD mouse model. Sanger sequencing was able to correct mRNA expression by 30% to 50%, providing a novel method for diagnosing DMD [58]. Several approaches, such as antisense oligonucleotides (ASOs), gene therapies, and stop codon read-through drugs, have been either approved or are currently under investigation for treating DMD disease [59].…”

Section: Duchenne Muscular Dystrophymentioning

confidence: 99%

Applications and Research Advances in the Delivery of CRISPR/Cas9 Systems for the Treatment of Inherited Diseases

Lu,

Zhang,

et al. 2023

IJMS

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The rapid advancements in gene therapy have opened up new possibilities for treating genetic disorders, including Duchenne muscular dystrophy, thalassemia, cystic fibrosis, hemophilia, and familial hypercholesterolemia. The utilization of the clustered, regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein (Cas) system has revolutionized the field of gene therapy by enabling precise targeting of genes. In recent years, CRISPR/Cas9 has demonstrated remarkable efficacy in treating cancer and genetic diseases. However, the susceptibility of nucleic acid drugs to degradation by nucleic acid endonucleases necessitates the development of functional vectors capable of protecting the nucleic acids from enzymatic degradation while ensuring safety and effectiveness. This review explores the biomedical potential of non-viral vector-based CRISPR/Cas9 systems for treating genetic diseases. Furthermore, it provides a comprehensive overview of recent advances in viral and non-viral vector-based gene therapy for genetic disorders, including preclinical and clinical study insights. Additionally, the review analyzes the current limitations of these delivery systems and proposes avenues for developing novel nano-delivery platforms.

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Section: Duchenne Muscular Dystrophymentioning

confidence: 99%

Applications and Research Advances in the Delivery of CRISPR/Cas9 Systems for the Treatment of Inherited Diseases

Lu,

Zhang,

et al. 2023

IJMS

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“…Some studies, however, point to limitations of the CRISPR/Cas9-mediated editing of the DMD gene. Particularly, potentially therapeutic excision of exons 6 and 7 in a mouse model carrying an out-of-frame deletion mutation of exons 8–34 resulted in synthesis of corrected mRNA but only low-level production of truncated dystrophin, presumably due to low protein stability [ 173 ]. In contrast, an increased amount of Dp71 variant with an altered C-terminus (Dp71f variant, without exon 78) was observed at the sarcolemma, shown previously to modify the dystrophin function [ 174 ].…”

Section: Gene Editing With Crispr/cas9mentioning

confidence: 99%

Dystrophin- and Utrophin-Based Therapeutic Approaches for Treatment of Duchenne Muscular Dystrophy: A Comparative Review

Szwec,

Kapłucha,

Chamberlain

et al. 2023

BioDrugs

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Duchenne muscular dystrophy is a devastating disease that leads to progressive muscle loss and premature death. While medical management focuses mostly on symptomatic treatment, decades of research have resulted in first therapeutics able to restore the affected reading frame of dystrophin transcripts or induce synthesis of a truncated dystrophin protein from a vector, with other strategies based on gene therapy and cell signaling in preclinical or clinical development. Nevertheless, recent reports show that potentially therapeutic dystrophins can be immunogenic in patients. This raises the question of whether a dystrophin paralog, utrophin, could be a more suitable therapeutic protein. Here, we compare dystrophin and utrophin amino acid sequences and structures, combining published data with our extended in silico analyses. We then discuss these results in the context of therapeutic approaches for Duchenne muscular dystrophy. Specifically, we focus on strategies based on delivery of micro-dystrophin and micro-utrophin genes with recombinant adeno-associated viral vectors, exon skipping of the mutated dystrophin pre-mRNAs, reading through termination codons with small molecules that mask premature stop codons, dystrophin gene repair by clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (CRISPR/Cas9)-mediated genetic engineering, and increasing utrophin levels. Our analyses highlight the importance of various dystrophin and utrophin domains in Duchenne muscular dystrophy treatment, providing insights into designing novel therapeutic compounds with improved efficacy and decreased immunoreactivity. While the necessary actin and β-dystroglycan binding sites are present in both proteins, important functional distinctions can be identified in these domains and some other parts of truncated dystrophins might need redesigning due to their potentially immunogenic qualities. Alternatively, therapies based on utrophins might provide a safer and more effective approach.

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Applications and Research Advances in the Delivery of CRISPR/Cas9 Systems for the Treatment of Inherited Diseases

Lu¹,

Zhang²,

Li³

et al. 2023

Preprint

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The rapid advancements in gene therapy have opened up new possibilities for the treatment of genetic disorders, including Duchenne muscular dystrophy, Thalassemia, cystic fibrosis, Hemophilia, and Familial hypercholesterolemia. The utilization of the clustered regularly interspaced short palindromic repeats (CRISPR) - CRISPR-associated protein (Cas) system has revolutionized the field of gene therapy by enabling precise targeting of genes. In recent years, CRISPR/Cas9 has demonstrated remarkable efficacy in treating cancer and genetic diseases. However, the susceptibility of nucleic acid drugs to degradation by nucleic acid endonucleases, necessitates the development of functional vectors capable of protecting the nucleic acids from enzymatic degradation, while ensuring safety and effectiveness. This review aims to explore the biomedical potential of non-viral vector-explore CRISPR/Cas9 systems for the treatment of genetic diseases. Furthermore, it provides a comprehensive overview of recent research advances in viral and non-viral vector-based gene therapy for genetic disorders, including insights from preclinical and clinical studies. Additionally, the review analyzes the current limitations of these delivery systems and proposes avenues for the development of novel nano-delivery platforms.

show abstract

CRISPR-Cas9 correction in the DMD mouse model is accompanied by upregulation of Dp71f protein

Cited by 3 publications

References 74 publications

Applications and Research Advances in the Delivery of CRISPR/Cas9 Systems for the Treatment of Inherited Diseases

Applications and Research Advances in the Delivery of CRISPR/Cas9 Systems for the Treatment of Inherited Diseases

Dystrophin- and Utrophin-Based Therapeutic Approaches for Treatment of Duchenne Muscular Dystrophy: A Comparative Review

Applications and Research Advances in the Delivery of CRISPR/Cas9 Systems for the Treatment of Inherited Diseases

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