The expanding field of precision gene editing is empowering researchers to directly modify DNA. Gene editing is made possible using synonymous technologies: a DNA-binding platform to molecularly locate user-selected genomic sequences and an associated biochemical activity that serves as a functional editor. The advent of accessible DNA-targeting molecular systems, such as zinc-finger nucleases, transcription activator-like effectors (TALEs) and CRISPR–Cas9 gene editing systems, has unlocked the ability to target nearly any DNA sequence with nucleotide-level precision. Progress has also been made in harnessing endogenous DNA repair machineries, such as non-homologous end joining, homology-directed repair and microhomology-mediated end joining, to functionally manipulate genetic sequences. As understanding of how DNA damage results in deletions, insertions and modifications increases, the genome becomes more predictably mutable. DNA-binding platforms such as TALEs and CRISPR can also be used to make locus-specific epigenetic changes and to transcriptionally enhance or suppress genes. Although many challenges remain, the application of precision gene editing technology in the field of nephrology has enabled the generation of new animal models of disease as well as advances in the development of novel therapeutic approaches such as gene therapy and xenotransplantation.
Zinc-finger nucleases, transcription activator-like effector nucleases and CRISPR systems are powerful tools that are enabling new applications of genome engineering in diverse systems.
Targeted double-stranded breaks in DNA activate diverse repair processes, such as non-homologous end joining, homology-directed repair and microhomology-mediated end joining, which can be utilized to modify the nucleotide sequence of DNA.
Use of non-nuclease genomic tools enables the editing of single bases and locus-specific epigenetic targeting to modify gene expression.
Applications of precision gene editing in nephrology include the generation of animal models to investigate kidney development and disease mechanisms as well as the development of targeted gene therapies.
Genome editing in the kidney is challenging owing to anatomical barriers to gene delivery, limitations of vector size and immune responses against viral vectors, modified cells and editing proteins.
Despite these challenges, precision gene editing has great potential to accelerate basic science in nephrology and to advance clinical practice through the development of novel therapies for renal diseases.
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The authors have received research funding from the Mayo Foundation and the US National Institutes of Health (grants GM63904 and P30DK084567 (S.C.E.) and P30DK090728 (C.R.S., P.C.H. and S.C.E.)).
The authors declare no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
- Programmable DNA nucleases
A DNA-binding platform that can be customized to bind to a specific DNA sequence and introduce a DSB in this targeted manner.
- Transposon elements
DNA sequences that can be translocated within the genome by transposase proteins.
- CpG site
A cytosine residue directly followed by a guanine residue in a DNA strand. Cytosine residues in CpG sites can be directly methylated by DNA methyltransferase.
- Morpholino oligomers
Synthetic modified oligomers that are capable of sterically inhibiting translation of specific RNAs in a targetable manner.
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