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PubMed2026

The present and future of nonviral delivery-based genome editing for hereditary hearing loss.

PURPOSE OF REVIEW: This review summarizes nonviral genome-editing delivery platforms for hereditary hearing loss, focusing on lipid nanoparticles (LNPs) and engineered virus-like particles (eVLPs), and discusses their advantages over adeno-associated virus-based delivery, as well as the barriers to clinical translation. RECENT FINDINGS: Recent advances have established LNPs as a clinically advanced nonviral platform, although challenges related to inner ear biodistribution, cell type specificity, endosomal escape, and immunogenicity remain to be addressed. In parallel, eVLPs have undergone substantial technical evolution, progressing from early low efficiency systems to advanced base editor- and prime editor-eVLP architectures that enhance cargo loading and editing efficiency. Extracellular vesicle-based genome editing has also emerged as an additional platform, although issues related to reproducibility, loading efficiency, and scalability remain major hurdles. SUMMARY: Nonviral genome editing platforms expand the therapeutic toolkit for hereditary hearing loss by enabling transient delivery of genome editors with potential safety advantages. Future efforts should focus on characterizing biodistribution and immunogenicity, refining cell type-specific tropism, and establishing scalable manufacturing processes to enable successful clinical translation.

Humans↗
PubMed2004

[Primary prevention for alcohol misuse in young people: a Cochrane Systematic Review].

The Cochrane Collaboration is an international no-profit organization established in 1992 in UK. The aim of the Collaboration is the conduction, update and dissemination of systematic reviews about health care. Systematic reviews are electronic documents systematically updated which synthesise the results of randomized controlled studies about treatments. The Cochrane Group on Drugs and Alcohol has the editorial base in Rome (Department of Epidemiology ASL RME) where the Coordinator, the Coordinating Editor and the Trial Search Coordinator, coordinate the work of seven editors based in several countries. As of April 2003 we published 17 reviews and 11 protocols of review. The systematic reviews on primary prevention for alcohol misuse in young people, was conducted by David Foxcroft and published by the group in 2002. The objectives of the systematic review were the identification and synthesis of the studies on psychosocial and educational programs for prevention of alcohol abuse and the assessment of long term interventions (over three years).

Adolescent↗
PubMed1991

Knowledge-based support for a physician's workstation.

We describe knowledge-based support for a Physician's Workstation prototype. Our knowledge base uses a qualitative simulation model of patient physiology. We present the motivation behind our design, discuss the components of the knowledge base, and show how the knowledge base supports a physician's workstation in the patient management process. We describe a graphical knowledge base editor used by the domain expert for knowledge acquisition, and a graphical knowledge base presenter which monitors the qualitative simulation during patient event processing.

Artificial Intelligence↗
PubMed2026

Base editing rescues a hereditary motor neuron disease in mouse and patient-derived iPSC organoid models.

In hereditary motor neuron diseases (MNDs), including forms of amyotrophic lateral sclerosis (ALS) caused by single-nucleotide variants, effective therapeutic strategies need to address both gain- and loss-of-function mechanisms. Genome editing-based gene therapy represents a promising approach for simultaneously targeting these mechanisms. To establish proof-of-concept for base editing in a hereditary MND, we targeted the P285L variant in the TRK-fused gene (TFG), which causes hereditary motor and sensory neuropathy with proximal dominant involvement (HMSN-P), a disorder that shares clinical and histopathological features with ALS. We identified the optimal adenine base editor by comparing candidate editors in HMSN-P patient-derived induced pluripotent stem cells (iPSCs). We then generated a transgenic mouse model expressing human TFG P285L and evaluated the selected editor by subpial delivery of adeno-associated virus (AAV) vectors to the spinal cord. AAV-mediated base editing prolonged survival, preserved motor neurons, and attenuated axon loss in ventral nerve roots. Treatment with the selected base editing vector reduced TFG aggregation and suppressed neuronal death in HMSN-P iPSC-derived neuromuscular organoids. Collectively, these findings support the therapeutic potential of base editing for hereditary MNDs.

AAV↗
PubMed2024

Introducing a hemoglobin G-Makassar variant in HSCs by in vivo base editing treats sickle cell disease in mice.

Precise repair of the pathogenic mutation in hematopoietic stem cells (HSCs) represents an ideal cure for patients with sickle cell disease (SCD). Here, we demonstrate correction of the SCD phenotype by converting the sickle mutation codon (GTG) into a benign G-Makassar variant (GCG) using in vivo base editing in HSCs. We show successful production of helper-dependent adenoviral vectors expressing an all-in-one base editor mapping to the sickle mutation site. In HSC-enriched cells from SCD patients, transduction with the base editing vector in vitro resulted in 35% GTG > GCG conversion and phenotypic improvements in the derived red blood cells. After ex vivo transduction of HSCs from an SCD mouse model and subsequent transplantation, we achieved an average of 88% editing at the target site in transplanted mice. Importantly, in vivo HSC base editing followed by selection generated 24.5% Makassar variant in long-term repopulating HSCs of SCD mice. The treated animals demonstrated correction of disease hallmarks without any noticeable side effects. Off-target analyses at top-scored genomic sites revealed no off-target editing. This in vivo approach requires a single non-integrating vector, only intravenous/subcutaneous injections, and minimal in vivo selection. This technically simple approach holds potential for scalable applications in resource-limiting regions where SCD is prevalent.

Animals↗
PubMed2025

Engraftment and persistence of HBB base-edited hematopoietic stem cells in nonhuman primates.

Sickle cell disease (SCD) is caused by a single nucleotide change in the β-globin gene that adenine base editors can convert to the nonpathogenic Makassar β-globin variant. Here, we evaluated the long-term efficiency and off-target editing potential of autologous Makassar base editing in three rhesus macaques as a step toward human translation. Base editing of CD34+CD90+ hematopoietic stem cells (HSCs) at the Makassar locus reached greater than 60% efficiency using a bystander nucleotide as a proxy for the sickle cell target in cells from healthy macaques. No impact on myeloid and erythroid colony formation was seen, and clonal analysis revealed that >90% of HSCs were edited, >20% with biallelic editing. After transplantation of autologous gene-edited HSCs, all three macaques rapidly recovered neutrophils, red blood cells, and platelets with stable editing of 25.6%, on average, observed across nucleated blood cells. Similarly, the bone marrow stem cell compartment maintained over 20% of cells harboring mono- or biallelic edits. Off-target editing was assessed at over 900 candidate sites, with editing observed at eight sites, but no selection for or impact of these edits was observed throughout engraftment. These data support further translation of base editing of autologous HSCs for the treatment of patients with SCD.

Animals↗
PubMed2026

Lipid-nanoparticle-mediated base editing of the trabecular meshwork rescues glaucoma in vivo.

Mutations in MYOC, the most common genetic cause of glaucoma, cause misfolded myocilin to accumulate in the endoplasmic reticulum (ER), leading to trabecular meshwork (TM) dysfunction, elevated intraocular pressure, and progressive vision loss. While gene editing offers curative potential, current delivery methods rely on viral vectors, which are limited by inflammation, off-target effects, and poor translatability. Here, we report a nonviral lipid nanoparticle (LNP) platform that enables selective in vivo delivery of mRNA encoding an adenine base editor and single guide RNA (LNP-ABE) to TM cells. A direct comparison of LNP-mCherry with lentiviral GFP revealed that LNPs outperform viral vectors, achieving markedly higher efficiency and greater selectivity for the TM without inducing ocular inflammation. In a Cre-inducible Tg.CreMYOCY437H glaucoma mouse model, LNP-Cre mRNA selectively induced mutant MYOC expression in the TM, faithfully recapitulating key disease features. A single administration of LNP-ABE achieved efficient on-target editing of mutant MYOC, reducing mutant myocilin protein by approximately 46%, decreasing aggregates, alleviating ER stress, and fully rescuing the glaucomatous phenotype in Tg.CreMYOCY437H mice. Importantly, no off-target editing or ocular toxicity was detected. These findings establish LNP-based mRNA delivery as a safe, efficient, and clinically translatable approach for TM-targeted genome editing with broad therapeutic potential in glaucoma.

Animals↗
PubMed2026

Base editing for precision therapeutics.

Base editing (BE), the precise installation of single-nucleotide changes in DNA or RNA without inducing double-strand breaks, holds substantial therapeutic promise for correcting single-nucleotide variants, which constitute more than half of the known pathogenic genetic variants. Recent advances have improved base editor specificity, efficiency, and delivery, enabling clinically oriented procedures. Clinically, BE has shown early success or strong translational promise in sickle cell disease, β-thalassemia, leukemia (via CAR T and epitope engineering), hypercholesterolemia (PCSK9 and ANGPTL3), alpha-1-antitrypsin deficiency, and glycogen storage disease type Ia. Key remaining challenges include bystander editing within the activity window, residual off-target DNA and RNA editing, delivery constraints (payload size, tissue targeting, and redosing limits), immunogenicity, and the need for durable long-term safety evidence across relevant cell types and disease contexts. Continued technological refinements, careful preclinical validation, and rigorous clinical assessment will be essential to fully realize BE's transformative potential in precision medicine.

Humans↗
PubMed2026

Single-cell mapping of regulatory DNA-protein interactions.

Gene expression is controlled by transcription factors (TFs), whose genome binding is shaped by chromatin accessibility and histone modifications, yet mapping these interactions, particularly those with weak affinity or a transient nature, in single cells remains technically challenging. To address this gap, we developed docking and deamination followed by sequencing (D&D-seq), a single-cell immuno-tethering technology for profiling DNA-protein interactions. D&D-seq couples an antibody-binding nanobody to a cytosine base editor, a combination that enables detection of weak or transient factor binding through targeted cytosine-to-uracil editing at protein-bound genomic sites. This approach is compatible with standard single-cell multi-omic workflows and therefore allows integrated analyses of gene regulation. Using assay for transposase-accessible chromatin using sequencing (ATAC-seq) and single-cell ATAC-seq (scATAC-seq), we assessed chromatin accessibility as a functional readout of TF activity, and by coupling D&D-seq with whole-genome sequencing, we captured CTCF binding in both active and inactive chromatin compartments.

Animals↗
PubMed2025

Translational reading frame determines the pathogenicity of C-terminal frameshift deletions in MeCP2: an alternative therapeutic approach.

Mutations in the MECP2 gene cause the severe neurological disorder Rett syndrome. A cluster of frameshift-causing C-terminal deletions (CTDs) lead to loss of ~100 amino acids at the C-terminus of the MeCP2 protein, and account for approximately 10% of RTT-causing mutations. The pathogenicity of C-terminal deletions (CTDs) is unexpected, as this C-terminal domain is non-essential in mice. Utilising databases of pathogenic and benign human MECP2 mutations, we find that some individuals with apparently typical CTDs do not exhibit Rett syndrome, confirming that C-terminal truncations are not intrinsically pathogenic. Using human DNA sequence data and mouse models, we demonstrate that pathogenicity results from a drastic reduction in MeCP2 levels and is determined by the presence of the short amino acid motif proline-proline-stop (-PPX) at the C-terminus, which results from a shift to the +2 reading frame. Individuals with CTDs that shift to the +1 frame avoid this motif and do not develop Rett syndrome. Mutating the stop codon of the PPX motif to tryptophan rescues MeCP2 expression and RTT-like phenotypes in a CTD mouse model. Finally, we demonstrate that an adenine base editor can efficiently introduce this tryptophan substitution in cultured cells. Overall, our findings uncover a simple and reliable prognostic distinction between benign and pathogenic CTDs and provide proof-of-concept for an editing strategy that potentially corrects all disease-causing CTD mutations.

Journal Article↗
PubMed2025

MitoScribe single-cell molecular recorder logs graded signaling dynamics into mitochondrial DNA.

Genetically encoded DNA recorders convert transient biological events into stable genomic mutations, offering a means to reconstruct past cellular states. However, current approaches to log historical events by modifying genomic DNA have limited capacity to record the magnitude of biological signals within individual cells. Here, we introduce MitoScribe, a mitochondrial DNA (mtDNA)-based recording platform that uses mtDNA base editors (DdCBEs) to write graded biological signals into mtDNA as neutral, single-nucleotide substitutions at a defined site. Taking advantage of the hundreds to thousands of mitochondrial genome copies per cell, we demonstrate MitoScribe enables reproducible, highly sensitive, non-destructive, durable, and high-throughput measurements of molecular signals, including hypoxia, NF-κB activity, BMP and Wnt signaling. We show multiple modes of operation, including multiplexed recordings of two independent signals, and coincidence detection of temporally overlapping signals. Coupling MitoScribe with single-cell RNA sequencing and mitochondrial transcript enrichment, we further reconstruct signaling dynamics at the single-cell transcriptome level. Applying this approach during the directed differentiation of human induced pluripotent stem cells (iPSCs) toward mesoderm, we show that early heterogeneity in response to a differentiation cue predicts the later cell state. Together, MitoScribe provides a scalable platform for high-resolution molecular recording in complex cellular contexts.

Journal Article↗
PubMed2025

RHO1-2 meganuclease gene editing targets human P23H rhodopsin-induced retinitis pigmentosa to rejuvenate rods and maintain cones.

Autosomal dominant retinitis pigmentosa (adRP) is an inherited retinal dystrophy characterized by progressive vision loss and eventual blindness. The P23H mutation (proline to histidine substitution at codon 23) in the rhodopsin (RHO) gene represents the most common form of adRP in North Americans. Currently, there is no cure for P23H adRP. Genome editing targeting the mutant RHO allele, leaving a functional wildtype (WT) allele, is an attractive approach for P23H adRP, as only one copy of RHO is needed for normal retinal function. We re-engineered an I-Cre meganuclease, called RHO1-2, to target a 22bp recognition sequence encompassing the mutation responsible for the p.P23H RHO mutation. In vitro, RHO1-2, cuts human P23H RHO but not WT RHO. In vivo, we delivered scAAV5:GRK1:RHO1-2 via subretinal injection in early-stage degeneration using the only large animal model of human p.P23H RHO adRP (TgP23H pigs). We tested RHO1-2 efficacy and durability, on retinal function using full-field electroretinograms and on retinal structure using spectral domain optical coherence tomography and immunohistochemistry. We observe that RHO1-2 treatment: arrests rod photoreceptor degeneration, resurrects rod-driven retinal function that does not exist in untreated TgP23H pigs, restores mislocalized rhodopsin expression and rebuilds rod inner and outer segments (IS/OS). Rod rescue maintains cones. A year after RHO1-2 treatment, we show that TgP23H pigs use rod-driven vision to navigate a maze. Our results demonstrate that genome editing via RHO1-2 meganuclease is a viable treatment to cure human p.P23H RHO adRP. They also suggest that meganuclease-based editors can be effective for other IRDs.

Journal Article↗
PubMed2025

Nondestructive Larval Genotyping of Danio rerio for Mitochondrial and Nuclear DNA Genetics.

The rapid advancement of nuclear and mitochondrial genomic editing tools has created an urgent need for efficient, nonlethal larval genotyping methods in zebrafish (Danio rerio) research. This study optimizes and validates a nondestructive proteinase K digestion method for mitochondrial and nuclear DNA genotyping while characterizing its impact on larval survival and gene expression. Using optimized protocol parameters, we demonstrate successful amplification of different mitochondrial and nuclear genetic loci with consistently high sensitivity. Molecular validation through PCR, restriction fragment length polymorphism analysis, and Sanger sequencing confirmed the specificity and reliability of the extracted DNA. The method successfully detected C-to-T base edits in the mt-tl1 gene introduced using the FusX TALE Base editor system, demonstrating its applicability to gene editing studies. Both 48-well and optimized 96-well formats were used, enabling this approach to be deployed at scale. This optimized method enables researchers to correlate genotypes with phenotypes in longitudinal studies while maintaining specimen viability, particularly valuable for investigating early-onset mitochondrial diseases, and utilizes standard laboratory equipment and reagents, facilitating widespread adoption in zebrafish research while adhering to ethical principles in reducing animal mortality.

Animals↗
PubMed2026

Gene therapy for genodermatoses at the crossroads of innovation and clinical translation.

Inherited genodermatoses are a heterogeneous group of rare monogenic disorders. Among these, epidermolysis bullosa (EB) and ichthyoses represent paradigmatic disorders characterized by severe skin fragility and hyperkeratosis, respectively, and impaired barrier function, often with profound effects on quality of life and systemic health. Current management remains largely palliative, underscoring the urgent need for disease-modifying therapies. Over the past 2 decades, advances in epithelial stem cell biology, vector engineering and genome editing technologies have transformed the therapeutic landscape for genodermatoses. Ex vivo gene therapy has provided the first proof that genetically corrected epidermal stem cells can achieve long-term tissue regeneration in EB skin patients, establishing a new paradigm for regenerative medicine. In parallel, the emergence of programmable genome engineering platforms, including CRISPR/Cas nucleases, base editors and prime editors, have enabled increasingly precise strategies for mutation-specific correction in both recessive and dominant disorders. Furthermore, the development of in vivo topical approaches is expanding the possibility of directly targeting the skin. Despite these advances, substantial translational barriers continue to limit broad clinical implementation. Efficient and durable targeting of epidermal stem cells within a highly regenerative tissue, together with safe delivery across the skin barrier, stringent control of off-target activity, scalable manufacturing and demonstration of long-term safety, remain major challenges for the clinical translation of these approaches. In this Review, we discuss the current state of gene therapy for genodermatoses, highlighting key clinical milestones, emerging genome editing technologies and next-generation delivery systems. We further examine the biological and regulatory challenges that need to be overcome to bridge the gap between experimental innovation and clinically accessible therapies for patients with inherited skin diseases.

epidermolysis bullosa (EB)↗
PubMed1989

Pulse, a PC-based graphics pulse sequence editor for NMR and MRI.

A flexible, personal computer (PC) based, screen-graphics oriented pulse sequence editor called PULSE has been developed for nuclear magnetic resonance (NMR) spectroscopy and magnetic resonance imaging (MRI). PULSE is used to set such NMR spectroscopic parameters as the delay and duration of rf transmit and receive gates, rf phase, sampling times, and such imaging parameters as rf pulse shape and gradient waveforms. The output of PULSE is a set of programs that can be loaded into a hardware pulse programmer. With PULSE, any desired NMR or MRI pulse sequence can be programmed quickly and easily.

Computer Graphics↗
PubMed2004

COBrA: a bio-ontology editor.

COBrA is a Java-based ontology editor for bio-ontologies that distinguishes itself from other editors by supporting the linking of concepts between two ontologies, and providing sophisticated analysis and verification functions. In addition to the Gene Ontology and Open Biology Ontologies formats, COBrA can import and export ontologies in the Semantic Web formats RDF, RDFS and OWL.

Cell Physiological Phenomena↗
PubMed2003

The development of variable MLM editor and TSQL translator based on Arden Syntax in Taiwan.

The Arden Syntax standard has been utilized in the medical informatics community in several countries during the past decade. It is never used in nursing in Taiwan. We try to develop a system that acquire medical expert knowledge in Chinese and translates data and logic slot into TSQL Language. The system implements TSQL translator interpreting database queries referred to in the knowledge modules. The decision-support systems in medicine are data driven system where TSQL triggers as inference engine can be used to facilitate linking to a database.

Artificial Intelligence↗
PubMed1995

Computer graphics editor GSE and some of its applications in morphology.

A simple, vector-based graphics editor, designed for experimental data presentation, schematics, large structured chemical formulae etc. in a modest IBM PC, MS DOS environment is described. Its applications in semi-automatic image analysis, especially in the implementation of design-based stereological methods for estimating global geometrical characteristics of studied samples and in 3D volume reconstruction from serial sections are discussed.

Computer Graphics↗