Amazing stuff!
"... Using bacterial retrons, this method can "reno" multiple dangerous mutations simultaneously, far more efficiently than previous gene-editing methods that might succeed against a single mutation, but are powerless against additional mutations not identical to the first. ..."
"Some genetic disorders—such as cystic fibrosis, hemophilia and Tay Sachs disease—involve many mutations in a person’s genome, often with enough variation that even two individuals who share the same disorder might have a different combination of mutations. Complexities like these make it challenging to develop broadly applicable gene therapies for these disorders.
Researchers ... now have developed an improved method of gene editing that is precise, more efficient than other similar methods and can correct many disease-causing mutations at once in mammalian cells. They also demonstrated its effectiveness in correcting scoliosis-causing mutations in zebrafish embryos. The new method uses genetic elements from bacteria called retrons that help protect the microbes from viral infection. This is the first time researchers have corrected a disease-causing mutation in vertebrates using retrons, raising hopes of new gene therapies for human disorders. ..."
From the abstract:
"Retrons can produce multicopy single-stranded DNA in cells through self-primed reverse transcription. However, their potential for inserting genetic cargos in eukaryotes remains largely unexplored.
Here we report the discovery and engineering of highly efficient retron-based gene editors for mammalian cells and vertebrates.
Through bioinformatic analysis of metagenomic data and functional screening, we identify retron reverse transcriptases that are highly active in mammalian cells. Rational design further improves the editing efficiency to levels comparable with conventional single-stranded oligodeoxynucleotide donors but from a genetically encoded cassette.
Retron editors exhibit robust activity with Cas12a nuclease and Cas9 nickase, expanding the genomic target scope and bypassing the need for a DNA double-stranded break.
Using a rationally engineered retron editor, we incorporate a split GFP epitope tag for live-cell imaging.
Lastly, we develop an all-RNA delivery strategy to enable DNA-free gene editing in cells and vertebrate embryos. This work establishes retron editors as a versatile and efficient tool for precise gene editing."
New Gene-Editing Tech Holds Promise for Treating Complex Genetic Diseases (original news release) "Advanced biotechnology repurposes two bacterial immune systems to correct large stretches of DNA."
Discovery and engineering of retrons for precise genome editing (no public access)
Discovery and Engineering of Retrons for Precise Genome Editing (preprint from July 2024, open access)
Figure 1: A metagenomic survey reveals highly active RTs in mammalian cells.
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