Gene therapy for Friedreich ataxia: Too much, too little, or just right?

Payne, R. Mark

doi:10.1016/j.omtm.2022.02.008

Cited by 2 publications

(2 citation statements)

References 9 publications

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“…For instance, once gene therapy has been delivered into a target tissue, it is difficult to regulate the levels of expression. Tight and appropriate regulation of healthy gene expression is essential for alleviating many diseases; too much expression may have toxic effects, and too little expression may not impart the intended benefits of the therapy (5,6). In contrast, Splice Editing directly rewrites large segments of an already highly and homeostatically regulated gene product.…”

Section: Discussionmentioning

confidence: 99%

“…Exon exchange via trans-splicing is particularly relevant for monogenic diseases with high allelic diversity since it could, in principle, repair a large spectrum of pathogenic variants in RNA including single nucleotide polymorphisms (SNPs) and large insertions and deletions (indels). As therapeutic changes induced by trans-splicing would be transient and expression of the engineered trans-spliced gene product would remain under endogenous regulation, trans-splicing is predicted to possess a superior safety profile compared to DNA editing and gene therapy (5,6). In contrast, methods using CRISPR-based DNA editing mutagenesis must be carefully designed and evaluated to avoid adverse outcomes.…”

Section: Introductionmentioning

confidence: 99%

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Programmable multi-kilobase RNA editing using CRISPR-mediated trans-splicing

Borrajo,

Javanmardi,

Griffin

et al. 2023

Preprint

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Current gene editing approaches in eukaryotic cells are limited to single base edits or small DNA insertions and deletions, and remain encumbered by unintended permanent effects and significant challenges in the delivery of large DNA cargo. Here we describe Splice Editing, a generalizable platform to correct gene transcripts in situ by programmable insertion or replacement of large RNA segments. By combining CRISPR-mediated RNA targeting with endogenous cellular RNA-splicing machinery, Splice Editing enables efficient, precise, and programmable large-scale editing of gene targets without DNA cleavage or mutagenesis. RNA sequencing and measurement of spliced protein products confirm that Splice Editing achieves efficient and specific targeted RNA and protein correction. We show that Splice Editors based on novel miniature RNA-targeting CRISPR-Cas systems discovered and characterized in this work can be packaged for effective delivery to human cells and affect different types of edits across multiple targets and cell lines. By editing thousands of bases simultaneously in a single reversible step, Splice Editing could expand the treatable disease population for monogenic diseases with large allelic diversity without the permanent unintended effects of DNA editing.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Programmable multi-kilobase RNA editing using CRISPR-mediated trans-splicing

Borrajo,

Javanmardi,

Griffin

et al. 2023

Preprint

View full text Add to dashboard Cite

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Friedreich's ataxia: new insights

Krasilnikova,

Humphries,

Shinsky

2023

Emerging Topics in Life Sciences

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Friedreich ataxia (FRDA) is an inherited disease that is typically caused by GAA repeat expansion within the first intron of the FXN gene coding for frataxin. This results in the frataxin deficiency that affects mostly muscle, nervous, and cardiovascular systems with progressive worsening of the symptoms over the years. This review summarizes recent progress that was achieved in understanding of molecular mechanism of the disease over the last few years and latest treatment strategies focused on overcoming the frataxin deficiency.

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Gene therapy for Friedreich ataxia: Too much, too little, or just right?

Cited by 2 publications

References 9 publications

Programmable multi-kilobase RNA editing using CRISPR-mediated trans-splicing

Programmable multi-kilobase RNA editing using CRISPR-mediated trans-splicing

Friedreich's ataxia: new insights

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