IL-15 boosts Mesothelin- and CD70-CAR NK cell potency in PDAC without added benefit from dual targeting

CAR NK therapy was explored for pancreatic cancer by targeting tumour cells and fibroblasts. Although, IL-15 armoured MSLN- and CD70-CAR Nk cells demonstrated in vitro acitivity alone, pooled dual targeting failed to enhance cytolysis in advanced models, highlighting limits of dual strategies and the need for improved CAR NK engineering.

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Evaluation of pharmacological readthrough and base editing for ANK1 nonsense mutations in an erythroid model of hereditary spherocytosis

Using engineered erythroid K562 models carrying ANK1 p.R281X or p.Q744X, Li and colleagues show that translational readthrough-inducing drugs partially restore ankyrin-1 expression and cellular phenotypes, whereas adenine base editing directly corrects these variants and restores near-wild-type phenotypes, providing proof of concept for two molecular intervention strategies for hereditary spherocytosis.

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ESCRT-I complex enhances therapeutic efficacy of antisense oligonucleotide drugs by regulating endosomal escape and glucose homeostasis

Nguyen and colleagues identify ESCRT-I as a key regulator of antisense oligonucleotide efficacy. VPS23 suppression enhances endosomal escape, reduces intracellular glucose level through GLUT2 regulation, and improves ASO and siRNA activities without affecting cellular uptake, revealing a metabolic–endosomal mechanism that can be exploited to optimize RNA therapeutics.

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From Epigenetic Mark Detection to Rational Design of Epigenetic Editing Strategies

Faiq and colleagues examine how epigenetic mark detection can guide the rational design of programmable epigenetic editing strategies. They highlight advances in locus-specific targeting and effector selection, positioning reversible epigenome reprogramming as a promising therapeutic approach for monogenic and complex multifactorial diseases.

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A modified cyclosporine enhances lentivector transduction ex vivo and in vivo by degrading IFITM3

Cellular antiviral defences limit lentivector gene delivery. The authors describe lentivector transduction enhancement via inhibition of antiviral IFITM3 by novel inhibitor BG147. BG147 has activity ex-vivo in human stem cells and in-vivo in mouse subretinal cells, driving IFITM3 degradation via lysosomes. BG147 can expands lentivector utility and reduce treatment costs.

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Targeting the MNK1-MYH9 Axis Blocks YAP1 Recruitment to Prevent Thrombosis and Platelet Activation-Induced NETosis

MNK1 acts as a structural shield on MYH9, preventing YAP1-mediated platelet activation. Developing MD2 to lock this MNK1-MYH9 complex introduces a safe antithrombotic strategy, shifting the therapeutic paradigm from kinase inhibition to stabilizing protein-protein interactions against immunothrombosis

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Antisense Oligonucleotide Selection Scheme for Rare Duchenne Muscular Dystrophy Mutations: Application to DMD Exon-16 Skipping

Guiraud-Geoffroy and colleagues present a rapid methodology to identify antisense oligonucleotides (AONs) targeting rare Duchenne muscular dystrophy mutations. Exemplified by the case of DMD exon-16 skipping, the strength of this approach lies in its ability to prequalify candidates and eliminate unsuitable leads early, before animal testing, thereby minimizing both time and costs

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The “dark proteome” comes of age

A longstanding debate has been whether the human proteome codes for more than the approximately 19,500 canonical protein-coding genes predicted by the human genome. A recent study by Deutsch et al.1 has added powerful insights into this problem by developing a multidisciplinary approach through an international consortium (TransCODE) to discover and validate protein signatures mined from non-canonical open reading frames (ncORFs). They show that two classes of ncORFs, yielding “microproteins” and “peptideins,” can play a role in critical cellular processes and are unique HLA-presented peptides for immune recognition.

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Givinostat enhances antisense oligonucleotide efficacy in the mdx52 model of Duchenne muscular dystrophy

Antisense oligonucleotide-mediated exon skipping in Duchenne muscular dystrophy is limited by low dystrophin restoration, partly due to 5’-3’ DMD transcript imbalance and limited transcript availability. Combining HDAC inhibitor Givinostat with exon skipping enhanced dystrophin expression and muscle function, although the 5’-3’ transcript imbalance remained uncorrected.

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NF2 lacking exon 11 induced by antisense gene therapy is able to partially recover merlin deficiency in NF2-SWN iPSC-derived spheroid model

Using an iPSC-derived Schwann cell spheroid model of NF2-related schwannomatosis, the authors show that antisense-mediated skipping of NF2 exon 11 partially restores merlin expression in cells carrying truncating variants. Treatment normalizes NF2-related signalling as mTORC pathway and nuclear YAP, supporting exon skipping as a potential therapeutic strategy for NF2-related Schwannomatosis.

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ASGCT 2026 oral session meeting summary: AAV cell line development and engineering

The oral session on adeno-associated virus (AAV) cell line development and engineering was organized at the American Society for Cell and Gene Therapy (ASCGT) Annual Meeting in Boston on May 13, 2026. The triple transfection method enables rapid rAAV (recombinant AAV) production for clinical development but is limited by high plasmid costs, batch-to-batch variability, and plasmid-derived impurities. Although stable integration of the viral production components in host cells offers a promising alternative, constitutive expression of certain viral genes can result in cytotoxicity, presenting a major obstacle to the development of stable producer cell lines.

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An inducible signal 1 booster overcomes limited access to antigen for solid tumor cell therapy

A signal 1 booster (S1B) was designed to address the lack of antigen access that poses a unique challenge to CAR-T treatment of solid tumors. The lead S1B molecule is small-molecule inducible and improves CAR T cell survival independent of antigen exposure.

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Strategies to prevent HNSCC by chewing gum delivery of enzymes/antimicrobials to reduce carcinogenic acetaldehyde produced by pathogenic microbes

Acetaldehyde, well-known human carcinogen, is produced by yeast, aerobic/anaerobic bacteria isolated from oral cancer patient saliva. Acetaldehyde production shows dose-dependent increase by glucose or alcohol and is inhibited in yeast by plant-derived enzymes that disrupt fungal-cell-wall. Antimicrobial peptide inhibits acetaldehyde production by bacteria but requires plant-derived enzymes to disrupt extracellular-polymeric-substances

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Accelerated design of antiviral peptides to clamp down on emerging pathogens

The rapid generation of the SARS-CoV-2 mRNA vaccines during the recent COVID-19 pandemic was a dramatic demonstration of how quickly molecular data on an emerging pathogen can be used to counter its spread.1 As is now well known, the nucleotide sequence of the virus was used to deduce the amino acid sequence, model the structure of the spike protein, and predict an appropriate epitope to express for the vaccine. In this issue of Molecular Therapy, the approach described by Lozano-Garcia et al. could be a rapid and complementary form of pandemic response along with mRNA vaccines.

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A combinatorial EVs-miRNA signature mediates the anti-tumoral activity of NFAT3-regulated extracellular vesicles in aggressive cancers.

NFAT3-regulated extracellular vesicles deliver a combinatorial miRNA signature that suppresses proliferation and invasion in aggressive breast and pancreatic cancer models. This study identifies the underlying molecular programs targeted by the miRNA combination and supports extracellular vesicles as a promising platform for multi-target RNA-based cancer therapy.

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Simultaneous Quantitative Detection of Multiple Low-Frequency Variants by High-Dynamic-Range Capillary Electrophoresis

Hagiwara, Tamamura, and colleagues developed a multiplex high-dynamic-range capillary electrophoresis assay for simultaneous detection of low-frequency variants across multiple loci. By incorporating mobility-shift strategies, the assay achieves a practical balance among sensitivity, multiplexing capacity, cost, and operational simplicity, supporting implementation of disease-focused gene panels in clinical laboratory settings.

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Neurodevelopmental miR-135a-1-3p and miR-135b-3p promote long-distance axon regeneration after injury in the central visual pathway

Functions of neuronal miRNAs are not fully understood and no clinical treatments exist for regenerating damaged CNS axons. To address these barriers, Trakhtenberg and colleagues identified a neurodevelopmental miRNA mechanism for translation towards CNS injury treatment, by showing that mimics of developmentally-downregulated miR-135a-1-3p and miR-135b-3p regulate gene networks and axon regeneration.

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CD19×CD3 bispecific T cell engager treatment induces remission in experimental pemphigoid disease

Gross and colleagues demonstrate that CD19×CD3 bispecific T cell engagers, can selectively target autoreactive B cells and improve clinical outcomes in a mouse model of pemphigoid disease, highlighting their potential as a novel therapeutic strategy for autoimmune blistering disorders.

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The long non-coding RNA, CyKILRb, acts as a competing endogenous RNA for tumor suppressive microRNAs to augment oncogenic phenotypes via induction of the PIK3R2/PI3K/AKT axis

CyKILRb is a cytoplasmic long non-coding RNA that drives non-small cell lung cancer growth by acting as a competing endogenous RNA for miR-3151-5p, preventing repression of PIK3R2 and activating the PI3K/AKT pathway. Mutating the CyKILRb miRNA-binding site abolishes these effects, linking CyKILRb→PIK3R2→PI3K/AKT to proliferation, clonogenicity, tumor progression, and cisplatin resistance.

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Ad5/52s Fiber Substitution Alters Ad5 Tropism, Bioavailability, and Plasma Sensitivity

Replacing the Ad5 fiber with the Ad52 short fiber reprograms viral tropism toward CAR-independent targets, including Schwann cells, while markedly reducing liver transduction after systemic delivery, thus revealing how capsid engineering can simultaneously redirect tissue targeting and reshape systemic bioavailability and safety.

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Lineage-Tailored Vesicles from Human Retinal Ganglion-Like Cells Drive Metabolic Homeostasis and Bioenergetic Recovery in Glaucoma

Vishwakarma and colleagues demonstrate that small extracellular vesicles derived from lineage tailored human retinal ganglion-like cells restore mitochondrial and metabolic homeostasis in glaucomatous neurodegeneration. These vesicles reprogram retinal bioenergetics and promote mitochondrial homeostasis to enhance neuroprotection, offering a promising translational strategy for glaucoma and other optic neurodegenerative disorders.

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Triple AAV Intein-Mediated Gene Therapy Ameliorates Dystrophic Phenotype in MDC1A Mice

To overcome the strict packaging limits of AAV vectors, this study utilizes a triple-AAV system paired with orthogonal split inteins to reconstitute the exceptionally large LAMA2 protein. This scarless, multi-vector approach successfully rescues the dystrophic phenotype in vivo, offering a scalable platform for large-gene therapies

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Dysregulated Proline Metabolism Contributes to Retinal Fibrosis in Neovascular AMD: Therapeutic Potential of Prolyl-4-Hydroxylase Inhibition

Subretinal fibrosis causes irreversible vision loss in neovascular AMD. This study shows that proline metabolism, particularly P4HA1-mediated proline hydroxylation, is activated in JR5558 mice and human AMD tissues. Diethyl pythiDC reduced collagen turnover and fibrovascular lesion expansion, with potential added benefit when combined with aflibercept.

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CAR design equips diverse immune cells with unique antigen-specific activation identities

Using a human haematopoietic stem and progenitor cell-derived multilineage immune cell platform, this study demonstrates that CAR design elicits distinct activation programmes depending on immune lineage, revealing how receptor design and cell identity together shape signalling and transcriptional responses across diverse immune cells following antigen stimulation.

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Tissue-Specific Silencing of Synthetic mRNAs By De-Targeting Elements Maps Vaccination-Competent Tissues, and Allows Cas9 De-Immunization

Sasso and colleagues leveraged the organ-specific miRNAs, by engineering synthetic mRNAs vaccines containing miR target sites to generate a functional map of immunologically competent organs. This work lays the foundation for novel vaccines designed to target the most immunologically proficient organs. They subsequently applied this approach to deimmunize Cas9, rendering it immunologically masked.

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A Helicase-Fused Cas9 improves Large-Size Fragment Knock-in

By fusing MCM5, a subunit of the eukaryotic MCM2-7 helicase complex, to the N-terminus of spCas9 (MCCas), the MCCas fusion protein enhances large-size fragment knock-in via homologous recombination, reduces indels, and enables efficient large-size fragment insertions in human cells and rabbit embryos

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Synchronized Latency Reversal and Immune Clearance by a Multifunctional Fusion Protein Enables HIV-1 Reservoir Reduction

Latent HIV reservoirs evade both antiviral therapy and immune surveillance. Luo and colleagues develop a multifunctional fusion protein that couples reservoir reactivation with targeted immune engagement and clearance, offering a coordinated strategy for exposing and eliminating persistent HIV-infected cells.

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Capless self-amplifying mRNA vaccine induces dose-sparing protective immunity against HPAI clade 2.3.4.4 H5 virus in mice

Song and colleagues report an enterovirus-derived capless self-amplifying mRNA vaccine platform that uses IRES-mediated translation to eliminate 5′ capping. When encoding H5 hemagglutinin, CLsamRNA induces robust humoral and cellular immunity and dose-sparing protection against lethal H5N8 challenge in mice, supporting a distinct RNA vaccine architecture.

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Neutralization of Pathogenic PC-OxPL by AAV-Delivered scFv as a Therapeutic Strategy for Amyotrophic Lateral Sclerosis

Gomes-Duarte and colleagues identify PC-OxPL as contributors to ALS-related pathology, enriched in CSF-associated APOE and linked to TDP-43 dysfunction, transcriptomic alterations, and motor deficits. Neutralization with AAV-delivered PC-OxPL-VecTab® mitigated these effects in vitro and in vivo, supporting further investigation of PC-OxPL-targeted therapeutic strategies for ALS.

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