Targeted gene repair articles from across Nature Portfolio

Nucleic acid-based therapies offer an alternative to traditional cancer treatment modalities, with promising data beginning to emerge. In this Review, the authors describe the design and development of nucleic acid-based therapies administered virally and non-virally, including discussions of the advantages and disadvantage of each approach, as well as the role of patient-specific factors such as the tumour microenvironment, and consider the most promising future research directions.

An emerging therapeutic strategy is to suppress nonsense mutations with engineered suppressor tRNAs. Here, the authors show that the mRNA translation velocity is a key parameter determining the efficacy of suppressor tRNAs.

Here the authors describe a functional screening platform in human stem cells to identify and optimize protein-based gene editing additives that increase homologous directed recombination and have potential to improve gene therapy workflows.

Compared to traditional Cas9 nucleases prime editors (PEs) are less active. Here the authors use OrthoRep, a yeast-based platform for directed protein evolution to enhance the editing efficiency of PEs: they identify mutations that have a positive effect on kinetics and use this knowledge to generate an efficient in vivo PE.

Experiments in mice show that designed epigenome editors that contain domains of transcriptional repressors can enable stable epigenetic silencing of Pcsk9, a gene with a role in cholesterol homeostasis, without inducing DNA breaks.

Existing TadA-derived CBEs exhibit residual A•T-to-G•C editing activity and suffer from lower activity at several sequence contexts and with non-SpCas9 targeting domains. Here, the authors use phage-assisted evolution to evolve CBE6 variants that address these limitations.

Combining the precision of CRISPR’s DNA searching ability with the speed and scalability of electronics, we have developed an ‘electronic DNA search engine’, called a CRISPR–Chip, which not only enables DNA detection without amplification, but also showcases the untapped potential of merging molecular biology with nanomaterial electronics. Here, we discuss highlights and challenges on the journey from the initial idea to the commercialization of the CRISPR–Chip.

By applying the logic of conditional enzymes, we have developed a zinc-finger-dependent recombinase system, the editing activity of which is induced by zinc finger DNA binding. The system combines the precision of recombinases with the DNA target site programmability of zinc finger domains.

Prime editing in vivo is systematically improved with an eye to clinical translation.

The fusion of a programmable transcription-activator-like effector (TALE) protein with a nickase, in conjunction with a deaminase, enables efficient and strand-selective DNA base editing. This approach has the potential to advance our understanding and treatment of diseases associated with mutations in the mitochondrial or nuclear genome.

Pre-symptomatic gene editing in preclinical models of hypertrophic cardiomyopathy shows therapeutic promise; clinical studies are now needed to assess safety and efficacy in humans.