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#基因治疗/编辑

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Oct 14Wed
  1. Mol Cell64

    Structural basis of directionality control in large serine integrases.

    Eight structures of SPβ integrase-DNA complexes, at resolutions down to 3.15 Å, reveal how directionality is controlled along the integrative and excisive pathways. Recombination-induced conformational changes and RDF-mediated repositioning of the coiled-coil subdomain determine which DNA site pairs form active synaptic complexes and which product complexes become conformationally locked against back reactions. The excision synaptic complex is fundamentally different from the integration one, providing a framework for engineering improved genome editing tools.

  2. biorxiv.org50

    Biomarker-driven and gene-enhanced viral therapy for malignant peripheral nerve sheath tumor

    Loss of the PRC2 histone mark H3K27me3, common in high-grade MPNST, sensitizes tumors to the oncolytic HSV G47Δ, but also triggers a compensatory integrated stress response that blunts viral protein translation. Engineers built G47Δ² with tumor-regulated ICP34.5 expression (BIRC5-driven), limiting daily xenograft tumor-volume growth to 0.6% (95% CI -2.9–4.2%) versus 8.3% for G47Δ² and 22.5% for controls, though murine gastrointestinal toxicity reduced event-free survival.

Oct 13Tue
  1. nature.com60

    Tracing the origins of CRISPR–Cas

    VIPR systems, a family of RNA-guided DNA-targeting systems found mainly in bacteriophages, may be evolutionary precursors to class 1 CRISPR-Cas. Yoon and colleagues identified them through structure-based searches of the AlphaFold database and showed that small Vipr proteins bind VIPR RNAs with tandem repeats. The NN bases guide DNA targeting through a 'one-nucleotide skip' code, validated in vitro and by transcriptional repression in Escherichia coli, and reprogramming the NN sequences redirects targeting without a protospacer-adjacent motif.

    Why it matters: It points to evolutionary precursors of CRISPR-Cas and a targeting rule that could enable new programmable genetic manipulation tools.

Oct 12Mon
  1. Sci Adv64

    SMCHD1 is a target for gene activation therapy to treat Prader-Willi syndrome.

    SMCHD1 represses the entire Prader-Willi syndrome locus in neural lineages in both mice and humans, making it a candidate target for activating the silenced maternal copy of the disease genes. Deleting Smchd1 after early development in vivo activated PWS genes in disease-relevant mouse tissues including hypothalamus and improved phenotypes in a PWS mouse model. Genome-wide SMCHD1 binding aside, this postearly targeting appeared safe, supporting gene activation therapy for the underlying cause of PWS rather than individual symptoms.

    Why it matters: It identifies a molecular target that activates the silenced maternal allele and improves disease phenotypes in a PWS mouse model.

Oct 9Fri
  1. doi.org40

    Innovative niosome screening for efficient gene delivery in senescent primary umbilical cord stroma-derived MSCs

    DP20CQ niosomes, built with DOTMA and polysorbate 20 plus chloroquine, delivered genes more effectively than DP80CH formulations in Palbociclib-induced senescent UC-MSCs from four donors. At DOTMA/DNA ratios of 10/1 and 15/1, DP20CQ achieved the highest transgene expression in senescent UC-MSCs, surpassing Lipofectamine, with strong endosomal escape at 10/1 and no loss of cell viability. This positions niosomes as gene delivery vehicles for senescent cells in antiaging therapy.

Oct 2Fri
  1. Nature67

    Structural mechanism governing the directionality of bridge recombination.

    IS621 recombinase-bridge RNA complexes mediate excision less efficiently than insertion, and cryo-EM structures explain why: excision substrates adopt linear conformations forming an X-shaped structure, unlike the bent U-shape of insertion, which reduces top-strand exchange efficiency and explains the natural bias toward insertion. Both reactions are tuned by base pairing between bRNA handshake-guide dinucleotides and top strands. The work clarifies the full IS110 transposition cycle and guides design of programmable bridge-editing tools.

  2. nature.com61

    Reactivation of the embryonic ζ-globin gene ameliorates severe forms of α-thalassemia

    Reactivating the embryonic ζ-globin gene can ameliorate severe forms of α-thalassemia. Liu et al. identify cis-regulatory elements that silence ζ-globin in definitive erythroid cells, and gene-editing strategies targeting them restore ζ-globin expression to therapeutically relevant levels in mouse and human disease models. The work points to a new genome-editing approach for severe α-thalassemia.

    Why it matters: It identifies cis-regulatory silencers of ζ-globin and shows gene editing can reactivate it in disease models.

Oct 1Thu
  1. nature.com56

    Restoring hearing in people with a rare form of deafness

    A gene therapy delivering a functional OTOF gene to inner-ear hair cells improved hearing in around 80% of participants within 24 weeks in the CHORD clinical trial, which enrolled 24 participants aged between 10 months and 16 years with OTOF-associated hearing impairment. Each participant received Otarmeni as a one-time infusion, either in one ear or in both ears. In April, Otarmeni became the first gene therapy for hearing loss approved by the US Food and Drug Administration.

Sep 28Mon
  1. nature.com59

    Germline homologous recombination deficiency influences TP53 -mutant clonal hematopoiesis fitness during platinum and PARP inhibitor treatment

    Platinum chemotherapy drives DNA damage response gene-mutant clonal hematopoiesis more strongly than PARP inhibitors, an analysis of treatment-associated clone behavior shows. Carrying germline mutations that confer homologous recombination deficiency slowed the expansion of these clones during treatment. The findings separate the mutagenic pressure of the two drug classes and identify germline HR status as a modifier of TP53-mutant clone fitness.

    Why it matters: It distinguishes platinum from PARP inhibitor effects on clonal hematopoiesis and adds germline HR status as a modifier of clone expansion.

  2. nature.com45

    Cargo size matters when designing lipid nanoparticles for delivery of large gene editors

    Ionizable lipids screened with a gene-editor-sized messenger RNA yielded LC-1, a lipid that forms nanoparticles with a structure enhancing endosomal escape. LC-1 enabled efficient genome editing in the liver, lung and brain of mice, addressing the reduced performance lipid nanoparticles often show when carrying the large messenger RNAs that encode gene editors.

Sep 27Sun
  1. biorxiv.org54

    Targeted CRISPRi screening reveals unexpected resilience across the RNA polymerase III transcriptome

    An inducible CRISPR interference platform with a custom sgRNA library enabled gene-specific repression of RNA polymerase III-transcribed genes and Pol III machinery. Genome-wide screens in diploid fibroblasts and HEK293T cells uncovered several Pol III dependencies, with multiple initiator methionine tRNA genes among the strongest fitness dependencies. Glioblastoma models, however, remained largely insensitive to repression of both individual Pol III genes and core Pol III components despite efficient target knockdown, challenging the assumption that cancer cells uniformly depend on elevated Pol III activity.

    Why it matters: It shows glioblastoma models tolerate Pol III gene repression, contradicting the link between Pol III activity and cancer growth.

Sep 24Thu
  1. biorxiv.org42

    Convergent evolutionary loss of chemosensory and blood-feeding pathways in non-blood-feeding mosquitoes

    Comparing chromosome-level genomes and whole-brain reconstructions across seven mosquito species, including three independent non-blood-feeding lineages, reveals convergent loss of blood-feeding genes: Aegyptin, blood-activated serine proteases Chymotrypsin-1 and 2, a carboxylesterase, and multiple chemosensory receptor clades. Non-blood-feeding females also show reduced female-biased head gene expression and smaller antennal lobes. The work defines a compact gene set underlying a complex trait lost three times over roughly 200 million years.

    Why it matters: Convergent losses across three lineages pinpoint the genes and brain regions required for mosquito blood feeding.

Sep 15Tue
  1. Sci Adv64

    Engineering suppressor tRNAs for effective treatment of Duchenne muscular dystrophy.

    Engineered UAA suppressor tRNAs, delivered systemically with optimized AAV vectors and RNA polymerase III promoters, restored full-length dystrophin and recovered muscle strength and motor function in mice with nonsense mutations, at lower doses than AAV microdystrophin therapies. No adverse toxicology appeared, and proteome-wide analysis showed reversion of molecular pathophysiology. The approach targets the roughly 15% of DMD patients with nonsense mutations.

    Why it matters: First platform shown to restore full-length dystrophin rather than a truncated version, at lower doses than microdystrophin.

Sep 14Mon
  1. Nature69

    Creating bottom-up RNA transfer vehicles from synthetic protein assemblies.

    AI-designed protein assemblies combined with natural protein domains yielded more than 100 bottom-up RNA transfer vehicles with unique sizes and shapes, surpassing the RNA transfer efficiency of widely used delivery vehicles by several orders of magnitude. Tropism was programmed with computationally designed peptide binders, enabling delivery of therapeutically relevant cargo RNAs across cellular models. One vehicle's in vivo biodistribution was mapped in a mouse at near-single-cell resolution, confirmed as safe, and used for a gene-editing treatment strategy for Duchenne muscular dystrophy in patient-derived cells and a pig.

    Why it matters: Generative AI-designed protein assemblies outperform established RNA delivery vehicles and work in vivo.

  2. Sci Adv48

    Widespread atypical UV-induced mutations form in single-stranded DNA.

    UV light induces an extended array of noncanonical mutations in single-stranded DNA, including AT>AM, GT>GV, AC>AA, AT>TT, and TA>TT substitutions that resist photo-reversion and likely originate from atypical photoproducts. The work coupled temperature-induced telomeric end resection in yeast with serial UV irradiation and whole-genome sequencing. These ssDNA-specific lesions offer an additional damage-mediated route to oncogenic melanoma mutations such as BRAF V600E, which involves a GT>GA substitution.

    Why it matters: It explains how UV light can generate melanoma-driver mutations that canonical SBS7-type lesions do not account for.

Sep 11Fri
  1. Nat Biotechnol53

    Programmable promoter editing for precise control of transgene expression.

    DIAL is a modular framework for building editable promoters that tune transgene expression in fine, heritable steps. Recombinase-mediated excision of nested spacers between zinc finger transcription factor binding sites and the core promoter generates a tunable range of unimodal expression setpoints from a single promoter, with small-molecule temporal control. Lentiviral delivery produced multiple setpoints in primary cells and induced pluripotent stem cells, and enabled mapping of transgene levels to phenotype in direct conversion to induced motor neurons.

    Why it matters: Gives a general method for titrating and locking in transgene expression levels, useful wherever gene dosage matters.

  2. Nat Biotechnol56

    Engineered genomic attachment sites for site-specific recombinases enable high-efficiency integration in plants and human cells.

    Rationally engineered chimeric attachment sites boost Bxb1-mediated integration efficiency in human cells and plants. The attB(V111) variant achieved 51.9% integration in HEK293T cells (1.7-fold over wild-type attB) and 35.6% in rice protoplasts (4.4-fold), and paired with a Bxb1 catalytic-domain mutant delivered 31% integration of a CD19 CAR cassette and 25% of an ornithine transcarbamylase cassette in human cells. In rice, a 5.8 kb herbicide-resistance cassette integrated in 24% of regenerated plants, with heritable transmission to T1 plants.

    Why it matters: Engineered attachment sites substantially raise recombinase-mediated integration efficiency across plants and human cells.

Sep 10Thu
  1. Nature67

    Efficient and precise programmable DNA knock-in without double-strand breaks.

    CRISPR kilobase-scale nickase-targeting (KNIT) editing inserts DNA fragments from 0.7 kb to over 10 kb without double-strand DNA cleavage by coupling a Cas9 nickase with a DNA donor recruiting system. It achieves up to 89% efficiency, cuts indel rates, translocations and off-target editing, restores gene expression in mutant cells, and enables non-viral CAR-T engineering with antitumour activity in vitro and in mice. This shifts kilobase-scale knock-in away from double-strand-break editing.

    Why it matters: A break-free CRISPR method reaching 89% knock-in efficiency could change how cell therapies are engineered.

Sep 9Wed
  1. Nat Biotechnol67

    Design of optimized epigenetic regulators for durable gene silencing with application to PCSK9 in nonhuman primates.

    An optimized TALE-based epigenetic regulator, EpiReg-T, silenced PCSK9 in macaque liver with over 90% efficiency lasting 343 days after a single lipid nanoparticle dose, lowering LDL cholesterol. In mice, EpiReg-T reached 98% efficiency versus 64% for the initial dCas9-based design. Multiomic analyses showed minimal off-target effects in monkeys, mice and human-derived cells, and the platform can be retargeted to other genes by reengineering the DNA-binding domain.

    Why it matters: Durable, single-dose epigenetic PCSK9 silencing with minimal off-target effects in nonhuman primates moves epigenetic editing toward the clinic.

Sep 8Tue
  1. JCO Glob Oncol58

    Clinical Relevance of Genomics Defined WHO5 Subtypes of Pediatric B-ALL in the Context of Measurable Residual Disease-Directed Risk-Based Therapy.

    WHO5 genomic classification identified subtype-defining abnormalities in 81.2% of 533 pediatric B-ALL patients treated on the ICiCLe-ALL-14 protocol, and a three-tier genomic risk model separated outcomes: 3-year EFS of 80.4%, 59.3%, and 45.8% for standard, intermediate, and high genomic risk (P < .0001). Genomic risk independently predicted EFS alongside postinduction MRD and ICiCLe risk on multivariable analysis, showing genomics can complement MRD-directed risk stratification.

    Why it matters: It shows WHO5 genomic subtypes add independent prognostic value to MRD-directed risk stratification in pediatric B-ALL.

  2. Nature76

    Non-genotoxic transplantation and in vivo selection through epitope editing.

    Epitope editing of KIT lets transplanted haematopoietic stem/progenitor cells escape anti-KIT monoclonal antibodies, enabling non-genotoxic in vivo conditioning and selection. Adenine base editing or prime editing introduced the KIT mutations together with BCL11A erythroid enhancer disruption to induce fetal haemoglobin for sickle cell disease and β-thalassaemia. Edited haematopoietic cells progressively enriched under anti-KIT selective pressure without clonal selection, allowing chemotherapy- and radiotherapy-free haematopoietic replacement.

    Why it matters: Replaces genotoxic transplant conditioning with antibody-based selection of edited HSPCs.

Sep 6Sun
  1. Cell56

    Recurrent patterns of TOP1-mediated neuronal genomic damage shared by major neurodegenerative disorders.

    Neurons from C9ORF72 ALS, C9ORF72 FTD, and Alzheimer's disease brains share a mutational process linked to topoisomerase 1. Single-cell whole-genome sequencing of 469 neurons showed a TOP1-like sIndel signature in 22% of ALS, 76% of FTD, and 61% of AD neurons versus 2% of controls, and RADAR assays confirmed increased TOP1-DNA covalent complexes. TOP1-mediated genome damage emerges as a shared mechanism of neuronal death across TDP-43 and tau proteinopathies.

    Why it matters: It identifies a single DNA damage mechanism shared by ALS, FTD, and Alzheimer's disease neurons.

Sep 4Fri
  1. Nat Biotechnol61

    Integrated epigenetic and genetic programming of primary human T cells.

    An all-RNA platform using CRISPRoff and CRISPRon epigenetic editors stably turns endogenous genes off or on in primary human T cells without sustained CRISPR expression. Silencing persists through cell divisions, T cell stimulations and in vivo adoptive transfer, without the cytotoxicity or chromosomal abnormalities of multiplexed Cas9 editing. Combined Cas12a-dCas9 engineering enabled CAR knock-in plus gene silencing, improving preclinical CAR-T tumor control and survival.

Sep 3Thu
  1. Nat Biotechnol62

    Adaptive model-guided protein evolution with sparse data optimizes compact eukaryotic genome editors.

    A model-guided engineering strategy for sparse data, EvoMax, produced a compact eukaryotic Fanzor2 nuclease variant, FanzMAX v3-hLa, that reaches up to 97% editing efficiency at the best-performing endogenous locus and a mean of ~33% across 19 endogenous loci. It outperformed enNlovFz2 and enCnCas12f1 by more than 2.6-fold and edited hPCSK9 in humanized mice. EvoMax combines Gaussian process regression, protein language models and inverse folding with iterative experimental profiling.

    Why it matters: It delivers a compact programmable nuclease with substantially higher mammalian editing efficiency than established compact editors.

Sep 2Wed
  1. nature.com71

    Engineered genomic attachment sites for site-specific recombinases enable high-efficiency integration in plants and human cells

    Rationally designed chimeric attB sites, built by recombining favorable sequence motifs from natural Bxb1 recognition sites, yield hyperactive attachment sites that boost recombinase-mediated targeted integration. From 144 designed attB variants, all recognized by Bxb1, the authors isolated variants driving efficient integration in human cells and rice, including a CD19-targeted CAR and an OTC cassette, with specificity confirmed by NGS and Nanopore sequencing and Mendelian inheritance in T1 rice lines.

    Why it matters: It offers a protein-free route to higher Bxb1 integration efficiency, lowering off-target risk for gene therapy and crop engineering.

  2. Sci Adv60

    Development of mitochondrial mutator pigs exhibiting increased mitochondrial DNA mutations and premature aging via prime editing.

    Prime editing combined with somatic cell nuclear transfer produced pigs expressing proofreading-deficient POLG, the catalytic subunit of DNA polymerase gamma. The pigs accumulated elevated somatic mitochondrial DNA mutation loads and showed premature aging phenotypes, including weight loss, anemia, increased apoptosis, up-regulation of senescence-associated markers, and shortened life span. The model offers a large-animal platform for studying mtDNA mutations in aging and testing therapies.

    Why it matters: First large-animal mitochondrial mutator model, made by prime editing, for preclinical aging research.

Sep 1Tue
  1. Nature60

    Automated prototyping of genetic codes.

    The tRNA 3' CCA end, long required for ribosomal recognition, tolerates mutation far more than expected: most non-CCA-3' tRNAs (otRNAs) are aminoacylated by all E. coli aminoacyl tRNA synthetases. The authors built AGENTEX, an automated robotic prototyping platform, and used it to run cell-free translation systems with compressed genetic codes of 34 aaRSs for 34 codons, evaluating two genetic codes with non-standard amino acid incorporation and reassignment of up to three codons. The work opens a route to designing translation systems and biopolymers with multiple non-standard monomers.

    Why it matters: It shows an automatable route to prototyping synthetic genetic codes, removing a key barrier to recoding organisms.

  2. Mol Cell63

    Stepwise DNA-unwinding gates TnpB genome-editing activity.

    DNA unwinding by Youngiibacter multivorans TnpB (Ymu1 TnpB) proceeds through a discrete partially unwound intermediate before a fully open state, which forms inefficiently and collapses without negative supercoiling, explaining the limited activity of natural TnpBs. The optimized variant H4W-L304F-V305R (Ymu1-WFR) stabilizes both states, enhancing DNA cleavage in vitro and increasing genome editing in plants. The work was done using biochemical and single-molecule assays.

    Why it matters: It defines the unwinding steps that limit TnpB editing and provides a variant that improves genome editing in plants.

Aug 31Mon
  1. Nat Biotechnol60

    Precise genomic integration of large DNA fragments by donor-directed annealing using prime editing.

    Prime assembly (PA) adapts prime editors to create annealing 3'-flaps on genome and donor DNA, enabling kilobase-scale insertion or megabase-scale excision at endogenous loci. It replaced endogenous sequences with a 2.9-kb donor at up to 57.8% efficiency in HEK293T cells with >90% accuracy, and integrated a chimeric antigen receptor cassette at up to 28.1% in primary human T cells. In mice, hydrodynamic delivery of a GFP donor yielded 4.3% integration in GFP-positive hepatocytes.

    Why it matters: It extends prime editing to precise large-fragment gene replacement with efficiencies high enough for therapeutic cell engineering.

Aug 24Mon
  1. nature.com70

    Adaptive model-guided protein evolution with sparse data optimizes compact eukaryotic genome editors

    A model-guided engineering pipeline (EvoMax) combining transfer-learning Gaussian process regression, ESM-2 and ESM-IF optimized Fanzor2 nucleases, compact eukaryotic genome editors, using sparse experimental data. Screening over 1,600 Fz2-like sequences yielded active orthologs including NaloFz2, and the resulting FanzMAX v3-hLa system reached up to 97% editing efficiency (mean ~33% across 19 loci) in bulk mammalian cells, roughly tenfold above baseline, with expanded TAM compatibility. In vivo editing of hPCSK9 in mice was achieved with single-AAV delivery.

    Why it matters: It gives laboratories a compact single-AAV-deliverable nuclease with near-homogeneous editing in bulk mammalian cells.

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