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Platform-based approaches for gene-editing therapies could markedly improve development efficiency, reduce costs and increase access for patients with rare diseases. Although gene editing has shown remarkable clinical success for a small number of Mendelian disease indications, broader adoption faces substantial hurdles. We propose strategies to overcome these challenges through modular platforms for nonclinical and chemistry, manufacturing and controls (CMC) data reuse, risk-based manufacturing quality, and streamlined umbrella clinical trials for regulatory efficiency and accelerated approval.

Parasitic genetic elements called transposons carry CRISPR machinery that is normally used against them by bacterial cells. This paradox has now been explained, with implications for gene-therapy research.

Useful new methods are being introduced to experimentally determine the genome-wide consequences of Cas9-based editing.

Hockemeyer et al. demonstrate targeted genetic modification of three genes in human embryonic stem cells and induced pluripotent stem cells using zinc-finger nucleases delivered on plasmids. They use the approach to generate a reporter cell line that monitors the pluripotent state, a drug-inducible overexpression system, and a reporter cell line for a gene that is not expressed in pluripotent stem cells.

Genome editing followed by sequencing has now been used to engineer and analyse every variation of several stretches of human DNA in living cells, providing insight into the function of each constituent nucleotide molecule. See Letter p.120

Transcription activator–like effector nucleases (TALENs) are a new technology for modifying the genome at specific loci of interest. Hockemeyer et al. now demonstrate the utility of TALENs for gene targeting in human pluripotent stem cells.

Tiling of regulatory DNA with mutations introduced by genome editing nucleases and linking the resulting alleles to a phenotypic readout allows the precise determination of functional sequence motifs within these regions.

The enzyme Cas9 is used in genome editing to cut selected DNA sequences, but it also creates breaks at off-target sites. Protein engineering has now been used to make Cas9 enzymes that have minimal off-target effects. See Article p.490

Zinc finger nucleases (ZFNs) are versatile tools for making precise modifications to genomes, and their use is now established in a range of model systems. ZFNs are also showing potential in human gene therapy, and several clinical trials are underway.

Genome editing with CRISPR–Cas9 is beginning to be used clinically; promising results to date inspire hope for broad medical impact and mindfulness about safety. A new study shows that when Cas9 cuts its target, a fraction of the time, the target chromosome experiences a breakage process known as chromothripsis, thus prompting efforts to understand the potential negative consequences of this phenomenon and ways to mitigate them.

Identification of residues critical for dimerization of the Fok1 nuclease domain of zinc-finger nucleases permits rational design of enzymes with improved cleavage activity and retained obligate heterodimerization. Also in this issue, Sander et al. report context-dependent assembly (CoDA), a simple method for designing zinc-finger nucleases.

Zinc finger protein transcription factors are developed for the selective silencing of the mutant huntingtin gene in human neurons in vitro and multiple animal models of Huntington’s disease in vivo while preserving expression of the wild-type allele.

Signaling by the tumor-suppressor protein p53 antagonizes CRISPR–Cas9 gene editing of human pluripotent stem cells and immortalized human retinal pigment epithelial cells.

This study extends the natural code by which transcription activation–like effector nucleases (TALENs) recognize DNA and uses the resulting expanded repertoire of repeat divariable residues (RVDs) to improve TALEN performance.

This study uses zinc-finger nucleases to target an inducible XIST transgene into chromosome 21 from trisomic Down’s syndrome pluripotent stem cells; the XIST RNA coats one copy of chromosome 21 and triggers whole chromosome silencing, suggesting the potential of this approach for studying chromosomal disorders such as Down’s syndrome and for research into gene therapies.

TALEs (transcription activator-like effectors) are transcription factors from the plant pathogen Xanthomonas that can be readily engineered to bind new DNA sequences of interest. Miller et al. use a truncated TALE linked to a nuclease domain to edit and regulate endogenous genes in human cells.

Pairing centres are specialized regions on worm chromosomes that mediate homologous pairing during meiosis. Sequence motifs that recruit proteins involved in pairing have been identified and they are sufficient for chromosome synapsis and segregation during meiosis.

This paper reports genetic manipulation of the malaria parasite Plasmodium falciparum with zinc-finger nucleases. It demonstrates gene disruption as well as replacement and site-specific editing of both an integrated reporter and an endogenous gene.

An unprecedented number of potentially disruptive therapeutic technologies are under development. Forward-looking policies, incentives and infrastructure are needed to harness these advances to provide effective and globally equitable healthcare.

Implementation of new pricing and business structures and improved licensing and manufacturing processes could reduce the per-patient cost of gene therapy tenfold.

Targeted genetic correction of hematopoietic stem cells is applied to X-linked chronic granulomatous disease.

Genome editing mediated by zinc finger nucleases can be used to generate fluorescently labelled proteins that are expressed at endogenous levels from their native genetic loci. Applying this technology to the clathrin light chain A and dynamin-2 loci reveals that clathrin-mediated endocytosis is more regular and efficient than previously thought.

To correct the market failure around pediatric cell and gene therapies, the authors propose a new model to lead late-stage development and commercialize these therapies outside traditional routes.

Genetic engineering in plants remains laborious and time consuming, with no precise genetic engineering methods comparable to those available in animal models. A new approach that relies on the use of designed zinc-finger nucleases is showcased here in maize, inducing herbicide tolerance that is stably inherited.