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At least 19 recordsLinked to original sources
PubMed2025

Screening rare genetic diagnoses for amenability to bespoke antisense oligonucleotide therapy development: A retrospective cohort study.

PURPOSE: To estimate the proportion of molecular genetic diagnoses in a real-world, phenotypically heterogeneous patient cohort that are amenable to antisense oligonucleotide (ASO) treatment. METHODS: We retrospectively applied the N=1 Collaborative's Variant Assessments toward Eligibility for Antisense Oligonucleotide Treatment guidelines to all diagnostic variants found by clinical genome-wide sequencing at a single pediatric hospital in 532 patients over a 6-year period. Variants were classified as either "eligible," "likely eligible," "unlikely eligible," or "not eligible" in relation to the different ASO approaches, or "unable to assess." RESULTS: In total, 25 unique variants across 26 patients (4.9% of 532 patients) were eligible or likely eligible for ASO treatment at a molecular genetic level, via canonical exon skipping (4), splice correction (3), or messenger RNA knockdown (19). Only 8 of these molecular genetic diagnoses were made within a year of symptom onset. After considering disease and delivery related factors, 11 diagnoses were still considered candidates for bespoke ASO development. CONCLUSION: A meaningful proportion of genetic diagnoses identified by genome-wide sequencing may be amenable to ASO treatment. These results underscore the importance of timely diagnosis, and the proactive identification and accelerated functional testing of genetic variants amenable to ASO treatments.

Humans↗
PubMed2025

Precision diagnostic and therapeutic interventions in rare genetic neurodevelopmental disorders.

Neurodevelopmental disorders (NDDs) include a broad spectrum of phenotypes spanning from intellectual disability (ID) to developmental delay (DD) and autism spectrum disorder (ASD). As neurodevelopmental phenotypes are a common presenting feature of an underlying genetic condition, professional medical organizations recommend genetic testing for all individuals with a NDD. When testing is pursued, identified genetic differences can lead to personalized clinical management with early diagnosis supporting the development of surveillance and intervention for co-occurring adverse health outcomes. Despite this, barriers to testing have prevented individuals from receiving a genetics referral and testing. Current therapeutic modalities including small molecule drugs, gene therapies, and antisense oligonucleotide therapies have emerged and shown promise in preclinical trials with therapeutic drugs gaining FDA approval. However, translational challenges are extensive, especially for identifying biomarkers of drug effects in the CNS. In this review, we discuss diagnostic approaches and clinical utility of genetic testing for rare genetic neurodevelopmental disorders, emerging development of individualized therapies, and progress for current therapeutics in addition to challenges with clinical translation and delivery. We will highlight opportunities for early diagnosis and treatment that are steadily gaining ground in favor of optimizing long-term health outcomes and improving quality of life for neurodiverse individuals. IMPACT: The path from genomics to therapeutics for neurodevelopmental disorders continues to present multiple opportunities and challenges. While emerging genome-wide sequencing and gene editing technologies deliver increased diagnostic yields and alternatives to life-long small molecule therapies, clinical translation has been challenging due to inherent cost and genetic heterogeneity. Limited access to genetic testing despite practice guidelines remains a barrier towards precision therapeutics for rare neurodevelopmental disorders, while pre-clinical investigations face obstacles when translating to human subjects. This review will summarize the impact of existing successes in diagnosis and therapeutics for neurodevelopmental disorders while highlighting ongoing challenges and areas of future opportunities.

Humans↗
PubMed2025

Clinically relevant pseudoexons of the GALNS gene and their antisense-based correction.

BACKGROUND: Biallelic pathogenic variants in the GALNS gene lead to Mucopolysaccharidosis Type IVA (MPS IVA), a rare lysosomal storage disorder. GALNS encodes the enzyme N-acetylgalactosamine-6-sulfatase, whose deficiency causes accumulation of glycosaminoglycans and leads to a broad spectrum of clinical manifestations primarily affecting the osteoarticular system. Several studies have shown that, in 10%-15% of patients with the biochemical phenotype of MPS IVA, standard molecular genetic testing fails to identify one or both causative variants in the GALNS gene. METHODS: We performed an in-depth investigation of GALNS' splicing, with a special focus on deep-intronic mutations that lead to activation of pseudoexons (PEs). Using bioinformatic tools, we analyzed all deep-intronic variants in GALNS available in public databases and subjected the most relevant ones to in vitro analyses using minigenes. RESULTS: We characterized eight PE-activating variants, one of which (c.121-210C > T) represents a recurrent pathogenic variant which has long been hidden behind the mask of a polymorphic variant. In addition, we demonstrate that GALNS' splicing can produce a diverse range of mRNA isoforms containing so-called wild-type PEs, which are present at low levels as part of non-productive splicing, and weak canonical exons which are prone to skipping. We show that PE-activating variants cluster within wild-type PEs, highlighting the need for closer scrutiny of these regions during genetic testing. Finally, we applied modified U7 small nuclear RNAs and circular RNAs to efficiently block the identified PEs and pave the way for personalized antisense-based therapy for MPS IVA patients. CONCLUSION: The results of this study expand the understanding of GALNS gene splicing, indicating hotspots for splicing mutations. The presented data not only help to increase the diagnostic yield for MPS IVA but also unveil new therapeutic approaches for a number of MPS IVA patients.

Humans↗
PubMed2026

Individualized antisense oligonucleotide treatment eligibility of patients living with neurodevelopmental diseases.

With advances in genetic diagnostic tools, pathogenic variants in patients with genetic diseases are being identified at an accelerated pace. For a subset of these patients, individualized genetic interventions such as antisense oligonucleotides (ASOs) would address the disease cause. These individualized, or n-of-1, ASOs are currently being clinically applied in dozens of cases but mainly in patients with neurodegenerative diseases. For neurodevelopmental disorders, however, several questions arise: (1) Are they treatable? (2) What is the appropriate time window? (3) Does the treatment effect justify the burden and risks of treatment? In this consensus statement, we argue for the case to consider the development of individualized ASO treatment for individuals living with neurodevelopmental diseases and discuss which aspects need to be taken into consideration.

Humans↗
PubMed2026

Early infantile developmental and epileptic encephalopathy: clinical spectrum, diagnosis, outcomes, and evolving treatment strategies.

Early infantile developmental and epileptic encephalopathy (EIDEE) is among the most severe epilepsy syndromes, with onset before three months of age and an estimated incidence of approximately 10 per 100,000 live births. The 2022 International League Against Epilepsy classification unified the historically distinct Ohtahara syndrome and early myoclonic encephalopathy under a single diagnostic framework defined by frequent drug-resistant tonic and/or myoclonic seizures, an abnormal neurological examination, and an abnormal interictal electroencephalogram-most characteristically a burst-suppression pattern. This narrative review synthesizes the clinical, electrophysiological, neuroimaging, genetic, and therapeutic literature within the EIDEE framework. The clinical phenotype is characterized by central hypotonia, postnatal microcephaly, cortical visual impairment, and age-dependent syndromic evolution toward infantile epileptic spasms syndrome or Lennox-Gastaut syndrome in the majority of patients. Electroencephalography remains essential for syndromic classification, while systematic metabolic screening and early trio whole-exome or whole-genome sequencing are central to the etiologic workup, achieving diagnostic yields of 60-65%. The most commonly identified genetic causes include STXBP1, KCNQ2, and SCN2A variants. Outcomes are poor overall and strongly etiology-dependent: vitamin-responsive disorders carry a substantially more favorable prognosis, whereas mortality reaches 25% in genetic cohorts. Genotype-guided pharmacotherapy is now applicable to a clinically meaningful subset of patients, with sodium channel blockers, potassium channel openers, and emerging antisense oligonucleotide therapies representing important therapeutic advances. Gene therapy trials are underway but have encountered early safety signals, underscoring the vulnerability of this population. Critical unmet needs include earlier molecular diagnosis, precision therapies targeting developmental outcomes beyond seizure control, and prospective international registries to characterize the long-term natural history of EIDEE.

Humans↗
PubMed2023

Single-swap editing for the correction of common Duchenne muscular dystrophy mutations.

Duchenne muscular dystrophy (DMD) is a fatal X-linked recessive disease of progressive muscle weakness and wasting caused by the absence of dystrophin protein. Current gene therapy approaches using antisense oligonucleotides require lifelong dosing and have limited efficacy in restoring dystrophin production. A gene editing approach could permanently correct the genome and restore dystrophin protein expression. Here, we describe single-swap editing, in which an adenine base editor edits a single base pair at a splice donor site or splice acceptor site to enable exon skipping or reframing. In human induced pluripotent stem cell-derived cardiomyocytes, we demonstrate that single-swap editing can enable beneficial exon skipping or reframing for the three most therapeutically relevant exons-DMD exons 45, 51, and 53-which could be beneficial for 30% of all DMD patients. Furthermore, an adeno-associated virus delivery method for base editing components can efficiently restore dystrophin production locally and systemically in skeletal and cardiac muscles of a DMD mouse model containing a deletion of Dmd exon 44. Our studies demonstrate single-swap editing as a potential gene editing therapy for common DMD mutations.

AAV↗
PubMed2026

An antisense antidote to oncogenic poison exons.

Splicing factors are frequently mutated in myeloid cancers, causing splicing aberrations that derail the expression of tumor suppressor genes. In SRSF2 mutated cancers, a key oncogenic splicing event is the inclusion of a "poison" exon that introduces an early stop codon in EZH2 mRNA, causing its destabilization. In this issue of Genes & Development, Islam et al. (doi:10.1101/gad.353628.126) define how mutant SRSF2 binding to the poison exon mediates its inclusion and identify an antisense oligonucleotide that represses the exon to restore EZH2 function and rescues hematopoietic defects. Thus, targeting of poison exons, many of which show protumorigenic and antitumorigenic properties, is a promising new avenue to treat cancer.

Oligonucleotides, Antisense↗
PubMed2026

Emerging Nucleic Acid-Based Therapies for Hypercholesterolemia with Focus on a New Modality, Liver-Directed miR-30c Analog C2.

Despite major advances in lipid-lowering therapies, a significant unmet need remains, particularly for patients with homozygous familial hypercholesterolemia (HoFH), severe heterozygous familial hypercholesterolemia (HeFH), and those who fail to achieve guideline-recommended LDL-C targets. Nucleic acid-based therapeutics have emerged as a transformative approach for treating hypercholesterolemia. Antisense oligonucleotides and small interfering RNAs (siRNAs) have demonstrated durable hepatic gene silencing and have led to approved therapies, while gene replacement and in vivo genome-editing strategies offer the potential for long-lasting, and possibly one-time, interventions. In parallel, microRNAs (miRNAs) have attracted increasing interest because of their ability to coordinately regulate multiple genes involved in lipoprotein metabolism, cholesterol transport, and lipid homeostasis. Human genetic studies further support the importance of miRNA-mediated regulation, exemplified by a rare ~2.5 kb deletion in the distal LDLR 3'UTR ("del2.5") that disrupts miRNA-binding sites and is associated with lifelong low LDL-C levels. This review summarizes recent advances, mechanisms of action, clinical progress, and remaining challenges across antisense oligonucleotides, siRNAs, gene therapy, genome editing, and emerging miRNA-based therapeutics for hypercholesterolemia. As an example of the latter approach, the liver-directed miR-30c analog C2 has demonstrated preclinical activity by coordinately reducing hepatic lipoprotein secretion and lipogenesis while enhancing cholesterol elimination, resulting in reduced LDL-C and atherosclerosis. However, it must be noted that these findings remain preclinical, and further optimization of delivery, pharmacokinetics, safety, and long-term efficacy will be required before clinical evaluation. Continued advances in RNA chemistry, targeted delivery, and genome engineering are expected to further expand the therapeutic landscape for dyslipidemia and cardiovascular disease.

Humans↗
PubMed2026

IRES-like element-mediated translation of vsp1S4(-) suppresses BmCPV replication via RNAi antagonism.

Double-stranded RNA (dsRNA) viruses are thought to express proteins exclusively from their sense strand, while the antisense strand serves primarily as a replication template. Whether the antisense strand harbors hidden coding potential remains largely unexplored. Here, by integrating ribosome profiling and mass spectrometry, we identify a conserved 78-amino acid microprotein, vsp1S4(-), encoded by an antisense small open reading frame (sORFs) of the Bombyx mori cypovirus (BmCPV) genome. We demonstrate that vsp1S4(-) translation is driven by a previously unrecognized IRES-like element. Functional characterizations reveal that vsp1S4(-) localizes to the plasma membrane and acts as a negative regulator of viral replication. Mechanistically, vsp1S4(-) interacts directly with the viral RNAi suppressor NSP8, competitively disrupting the NSP8-AGO2 complex. This action restores the host's antiviral RNAi response, thereby limiting viral proliferation. Our findings challenge the conventional view of dsRNA virus coding capacity, unveil a novel viral immune evasion and replication control mechanism, and highlight antisense-encoded microproteins as potential targets for antiviral therapy.

Animals↗
PubMed2026

Emerging Therapies for Angelman Syndrome.

Angelman syndrome (AS) is a complex neurogenetic disorder characterized by severe global developmental delay, motor dysfunction, and epilepsy, primarily resulting from the lack of functional ubiquitin protein ligase E3A (UBE3A) protein expression in neurons. While current management remains largely symptomatic, the therapeutic landscape for AS is rapidly evolving. Emerging strategies aim to restore UBE3A function through upstream interventions, such as gene replacement therapy or unsilencing of the imprinted paternal allele, which is present but transcriptionally silenced in neurons due to genomic imprinting. This imprinting is mediated by the distal portion of a long non-coding RNA known as the UBE3A-antisense transcript (UBE3A-ATS). This UBE3A-ATS has become a key therapeutic target, with several approaches developed to unsilence the paternal allele, including antisense oligonucleotides (ASOs), CRISPR-based editing, synthetic microRNA, and other modalities. To date, three ASO programs have demonstrated promising signals in early clinical development, with reported improvements in clinical outcomes and electroencephalography (EEG) biomarkers. Given the potential for improved outcomes with early intervention, the inclusion of AS in broader genomic newborn screening programs is currently being explored. An early-intervention approach, or combination of approaches, holds significant promise for transforming the lives of individuals affected by AS with outcomes dependent on their age or genotype.

Humans↗
PubMed2026

Target, silence, replace: a review on RNA-based drugs in modern medicine.

RNA therapies have evolved into a revolutionary approach in contemporary medicine for treating various diseases by directly targeting RNA molecules engaged in disease pathogenesis. These therapeutic agents regulate biological processes through diverse mechanisms, including modulation of RNA function and gene expression. Medical applications of RNA are greatly enhanced by its structure, adaptability, and capacity for targeted binding. Among these traits is its ability to bind to certain molecules unique to those chemicals. RNA-based treatments have emerged from advancements in the production, modification, and cellular transport of RNA molecules. Several RNA drugs have been approved whereas some are under trial for few diseases. RNA therapeutics can function at the level of RNAs, DNAs and proteins. The evolution of mRNA vaccines during the COVID-19 epidemic emphasizes the exciting potential of RNA therapies in the treatment of diseases. This article provides a comprehensive overview of the several forms of RNA therapies, including small-interfering RNA (siRNA), messenger RNA (mRNA), and antisense-oligonucleotides (ASOs), together with information on their action mechanisms and delivery strategies that improve cellular absorption and shield RNA molecules from degradation. Further, CRISPR-based editing of the genome can be employed for modification of target RNA sequences for various disorders. Development of RNA aptamers have also been identified as pivotal RNA-therapeutic candidate. Additionally, we have explained mechanistic details and examples of drugs approved for RNA therapy. Emphasizing their potential to enhance patient outcomes and fulfil unmet medical requirements, we also highlight the clinical development of RNA therapies in treating cancer and other infectious diseases.

RNA interference↗
PubMed2026

Tripled-Stranded Antisense Oligonucleotide for Biomarker-Activated Suppression of Essential Genes.

Conditional activation of antisense oligonucleotides (ASOs) is a promising strategy for selective suppression of cancer cells without affecting normal cells. In this study, we developed a tripled-stranded ASO (tsASO) that is rendered inactive through complexation with two additional oligonucleotides. The key innovation is the use of partial overlap between the parent ASO and the biomarker sequence, combined with toehold-mediated strand displacement, enabling precise conditional activation. The tsASO effectively triggered RNase H-mediated degradation of DYNC1I2 and DARS1 RNAs exclusively in the presence of the ERBB2 sequence. In cell-free systems, the tsASO demonstrated high cleavage efficiency (up to 81%), comparable to the parent ASO efficiency, with minimal background activity in the absence of the biomarker sequence, validating the concept at the molecular level. However, in cells using lipid-based transfection, the tsASO exhibited nonspecific cytotoxicity that did not correlate with biomarker presence or target gene expression. Detailed analysis showed no clear support for known sequence-driven toxicity mechanisms (CpG/TLR9, G-quadruplexes) in the nonimmune cell lines, suggesting that the primary limitation is intracellular delivery rather than the tsASO design. Future work should focus on optimizing delivery platforms to achieve controlled cellular uptake and biomarker-dependent release, unlocking the therapeutic potential of this conditional gene silencing approach.

Oligonucleotides, Antisense↗
PubMed2025

Gene regulation technologies for gene and cell therapy.

Gene therapy stands at the forefront of medical innovation, offering unique potential to treat the underlying causes of genetic disorders and broadly enable regenerative medicine. However, unregulated production of therapeutic genes can lead to decreased clinical utility due to various complications. Thus, many technologies for controlled gene expression are under development, including regulated transgenes, modulation of endogenous genes to leverage native biological regulation, mapping and repurposing of transcriptional regulatory networks, and engineered systems that dynamically react to cell state changes. Transformative therapies enabled by advances in tissue-specific promoters, inducible systems, and targeted delivery have already entered clinical testing and demonstrated significantly improved specificity and efficacy. This review highlights next-generation technologies under development to expand the reach of gene therapies by enabling precise modulation of gene expression. These technologies, including epigenome editing, antisense oligonucleotides, RNA editing, transcription factor-mediated reprogramming, and synthetic genetic circuits, have the potential to provide powerful control over cellular functions. Despite these remarkable achievements, challenges remain in optimizing delivery, minimizing off-target effects, and addressing regulatory hurdles. However, the ongoing integration of biological insights with engineering innovations promises to expand the potential for gene therapy, offering hope for treating not only rare genetic disorders but also complex multifactorial diseases.

Humans↗
PubMed2026

SOD1 Variants in Patients With Amyotrophic Lateral Sclerosis in Central Eastern Europe: From Genetic Testing to SOD1 Targeted Therapy.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is one of the most devastating fatal motor neuron diseases, characterized by progressive degeneration of motor neurons in the brain and spinal cord. A significant advance in ALS therapy was achieved with the recent European Medicines Agency approval of Tofersen, the first antisense oligonucleotide (ASO) specifically targeting SOD1 mRNA, a key genetic determinant of the disease. Yet, despite its clinical relevance, data on SOD1-ALS in Central Eastern Europe remain scarce. METHODS: Here, we present a multicentric study across six countries-Austria, Czechia, Poland, Hungary, Slovakia, and Slovenia-representing approximately 16% of the European Union's population. We report all pathogenic, likely pathogenic, and uncertain SOD1 variants, along with the phenotypic features, including heritability, age, site of onset, and survival. We also assessed the availability of genetic testing, counseling, and access to Tofersen therapy across the region. RESULTS: Out of 1200 patients with confirmed ALS, we identified 24 distinct pathogenic SOD1 variants in a total of 67 patients (median age at onset 47 [40-55] years), of whom 65.7% had familial ALS (fALS) and 34.3% had sporadic ALS (sALS). We characterized the associated phenotypes and reported that 42 patients are currently receiving Tofersen therapy. CONCLUSION: This study provides the first comprehensive overview of SOD1-ALS in Central Eastern Europe. Our findings underscore the importance of genetic testing and counseling, as well as equitable access to targeted therapies such as Tofersen to advance patient-specific care in this region.

Humans↗
PubMed2026

CRISPR-Enabled functional genomics in hPSCs-derived neural models for autism spectrum disorder.

Autism Spectrum Disorder (ASD) is a genetically heterogeneous neurodevelopmental condition in which hundreds of individually rare risk variants converge on a small number of shared biological pathways, including synaptic scaffolding, chromatin remodeling, excitation-inhibition balance, and cellular energy metabolism. Translating this genetic heterogeneity into mechanistic insight requires experimental systems capable of interrogating individual gene functions in human-relevant neural contexts at scale. CRISPR-enabled functional genomics in human pluripotent stem cell (hPSC)-derived neural models, spanning neural progenitors, cortical and inhibitory neurons, astrocytes, microglia, and brain organoids, provides precisely this capability. By integrating pooled perturbation screens with multimodal readouts including single-cell and spatial transcriptomics, chromatin accessibility profiling, proximity labeling proteomics, multi-electrode array electrophysiology, and metabolic flux analysis, these platforms enable systematic, causal mapping of ASD gene function at system resolution. Early applications have already revealed convergent mechanisms: BAF complex disruption expands the ventral progenitor pool and biases its fate toward oligodendrocyte and interneuron lineages; ADNP loss impairs microglial synaptic pruning through altered endocytic trafficking; and mTOR pathway dysregulation in PTEN- and TSC2-perturbed models links genetic risk directly to metabolic and mitochondrial dysfunction. Computational frameworks including MIMOSCA and SCEPTRE enable causal network reconstruction and pseudotime inference from these datasets, moving the field from gene lists toward pathway-level models of ASD pathobiology. Translational applications leverage isogenic iPSC panels and variant-level base and prime editing to stratify ASD variants by functional impact, informing gene therapy design for haploinsufficient targets such as CHD8 and SCN2A via AAV or antisense oligonucleotide delivery. Remaining challenges, including model developmental immaturity, batch variability, and the difficulty of modeling polygenic risk, are addressed by a roadmap integrating spatial perturbomics, AI-driven causal inference, and population-scale standardized biobanks. This review synthesizes the current state of CRISPR-based functional genomics in human stem cell neural models as a coherent experimental framework for converting ASD genetic associations into mechanistic understanding and therapeutic opportunity.

Humans↗
PubMed2026

RNA splicing and cardiovascular disease: a guide for cardiologists.

Alternative splicing (AS) is a fundamental RNA processing mechanism, which generates different RNA transcripts and consequently different protein isoforms from a single gene. This increases the diversity of proteins within an organism and can fine-tune biological processes. This review examines how cardiac-enriched RNA-binding proteins establish heart-specific splicing programs governing aspects of cardiac development, function, and disease. Developmentally, coordinated sarcomeric isoform switches underpin the foetal-to-adult transition and further isoform rewiring in ion channel and kinase genes determine electrophysiology and excitation-contraction coupling. AS contributes to the pathogenesis of several cardiomyopathies and emerging datasets suggest that pathological hypertrophy engages distinct splicing signatures compared with physiological hypertrophy. This review summarizes diagnostic and prognostic opportunities arising from bulk, long-read, and single-cell/nucleus transcriptomics, which resolve cell type-specific isoforms and disease-associated switches. Circulating RNA biomarkers (including splice ratios and circularRNAs) may signify myocardial remodelling and arrhythmic risk. Integrative approaches that link AS with proteomics and genomics improve variant interpretation, reveal previously unannotated protein isoforms, and enable tracking of disease progression and therapy response. Finally, an outline of therapeutic strategies to modulate AS in cardiovascular disease (CVD), including antisense oligonucleotides, small molecules, and genome-editing modalities (CRISPR, base, and prime editing), is provided. The major challenges that remain before splice-targeting therapeutics can be targeted to treat cardiovascular disease are highlighted. Lessons from neuromuscular indications establish clinical feasibility of splicing correction and motivate translation to cardiology. Together, mechanistic insight, biomarker development, and therapeutic innovation position RNA splicing as a tractable axis for precision cardiovascular medicine.

Humans↗
PubMed2026

Duchenne muscular dystrophy: from gene to gene-ius therapies.

Duchenne muscular dystrophy (DMD) is a severe X-linked neuromuscular disorder caused by mutations in the dystrophin gene that result in the absence of functional dystrophin, leading to progressive muscle degeneration, loss of ambulation, respiratory failure, cardiomyopathy, and premature mortality. Despite advances in multidisciplinary supportive care, DMD remains an incurable disease associated with substantial physical, psychosocial, and economic burdens. The monogenic nature of DMD and its well-defined molecular pathogenesis have made it a prime target for the development of precision therapies aimed at restoring dystrophin expression or modifying disease progression. This review provides an overview of the genetic and molecular mechanisms underlying DMD, summarizes its clinical manifestations and natural history, and discusses current standards of care. It further examines recent advances in disease-modifying therapeutic strategies, including exon-skipping antisense oligonucleotides, nonsense mutation readthrough agents, adeno-associated virus (AAV)-mediated micro-dystrophin gene replacement, and emerging genome-editing technologies such as CRISPR/Cas9. The review also highlights the limitations of existing treatments, including mutation specificity, variable efficacy, immune-related challenges, and uncertainties regarding long-term durability and safety. Finally, it considers future directions in therapeutic development, emphasizing the need for combination approaches, improved delivery systems, and next-generation gene-editing platforms to achieve more effective and lasting clinical outcomes. Collectively, these advances represent a paradigm shift in DMD management and offer renewed hope for improving survival and quality of life for affected individuals.

Humans↗
PubMed2026

Epilepsy of infancy with migrating focal seizures: A scoping review of clinical features, diagnostic testing including genetics, long-term outcomes, mortality, and current and emerging therapeutic strategies.

BACKGROUND: Epilepsy of infancy with migrating focal seizures (EIMFS) is among the most severe developmental and epileptic encephalopathies (DEEs), marked by intractable multifocal seizures migrating across both hemispheres, profound developmental arrest, and high early mortality. Advances in next-generation sequencing have revealed a heterogeneous genetic architecture dominated by KCNT1 gain-of-function variants across more than 30 implicated genes, creating opportunities for precision therapeutics. OBJECTIVE: To systematically map published evidence on the clinical, electrophysiological, neuroimaging, genetic, and therapeutic landscape of EIMFS, and to delineate critical knowledge gaps and future research priorities. METHODS: A scoping review was conducted following the Arksey and O'Malley framework, searching PubMed, Ovid MEDLINE, Embase, Cochrane Library/CENTRAL, and ClinicalTrials.gov. RESULTS: Of 643 articles screened, 89 met inclusion criteria. Beyond confirmation of the canonical electroclinical phenotype, several gaps emerged: neonatal versus post-neonatal onset stratification by genetic etiology remains largely uncharacterized; genotype-specific EEG biomarkers are lacking except for a single small KCNT1 study; and the clinical significance of atypical EEG features-including burst suppression and hypsarrhythmia-is undefined. Neuroimaging literature documents progressive cerebral atrophy and myelination abnormalities without quantitative volumetry, diffusion tractography markers, or attribution to seizure burden, medication effects, or underlying etiology. Genetic diagnostic yield was 70-80%, with KCNT1 accounting for 30-50% of solved cases; however, genotype-outcome stratification is limited. Seizures were broadly refractory; potassium bromide, ketogenic diet, cannabidiol, and quinidine (in KCNT1-confirmed cases) showed partial efficacy. Emerging precision approaches include sodium channel blockers for SCN2A gain-of-function variants, novel small molecules, fluoxetine, antisense oligonucleotides, and divalent siRNA targeting KCNT1. Systemic-to-pulmonary collateral circulation causing severe cardiopulmonary complications was reported across multiple cases, yet no consensus screening protocol exists. CONCLUSIONS: EIMFS remains one of the most refractory epilepsy syndromes of infancy. Precision genetic diagnosis is essential to guide targeted therapy. International collaborative registries, standardized outcome measures, genotype-stratified biomarker studies, and rapid point-of-care genomic testing are urgently needed to advance evidence-based care for this highly vulnerable population.

Humans↗