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Posts by Molecular Therapy Family of Journals

Single-cell transcriptomic atlas-guided NRG3-ERBB4 axis enhances the efficacy of chemo-immunotherapy during induction phase in high-risk neuroblastoma Induction-phase chemo-immunotherapy with naxitamab activates the NRG3-ERBB4 axis, which rewires ganglioside metabolism, enhances effector cell cytotoxicity, and identifies ERBB4 as a target for high-risk NB.

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Arrayed dual-gRNA CRISPR Screening Platform for C9orf72 Repeat Expansion Excision in Patient iPSCs Clelland and colleagues advance CRISPR gene therapy for C9orf72-FTD/ALS by screening gRNA pairs for excision of C9orf72’s intronic repeat region and selective excision of the mutant allele in patient iPSCs. They optimize off-target analysis in patient iPSCs using three unbiased nomination methods and a novel whole genome sequencing validation pipeline.

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A Primer On Prime: A Prime Editing Update from Advances to First-in-Human Trial Lushington and colleagues synthesize the rapidly evolving prime editing landscape, from pegRNA and editor engineering to dual-pegRNA and integrase/recombinase platforms, and connect these advances to safety frameworks and the first in-human study. The review provides a clinically oriented roadmap for translating precision genome rewriting into therapies.

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In vivo systematic detection of the outcomes of CRISPR/Cas9 mediated DNA repair in skeletal muscle stem cells This study profiles CRISPR/Cas9 repair outcomes in skeletal muscle stem cells in vivo, revealing the occurrence of anticipated small indels and prevalence of large on-target modifications, including large deletions, AAV integrations, and endogenous genomic insertions. These findings provide critical insights for improving the safety of CRISPR/Cas9-based gene therapies.

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Fibulin-4 expressed in metastatic breast cancer is a target of peptide-based imaging probes and experimental therapeutics Metastatic disease remains difficult to detect and treat. Kolonin and colleagues develop BLMP6, a cyclic peptide that homes to breast cancer metastases via binding to fibulin-4, which is upregulated in invasive tumors. Radiolabeled BLMP6 enables detection of metastases, and a BLMP6–MMAE conjugate suppresses metastatic growth and improves survival in mice, supporting fibulin-4–targeted strategies for imaging and therapy of metastatic cancer.

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Dual inhibition of intercellular adhesion molecule-1 and nucleolin reduces RSV infection efficiency in human respiratory organoids Takayama and colleagues used human induced pluripotent stem cell-derived respiratory organoids to investigate host factors that facilitate respiratory syncytial virus (RSV) entry. They identified intercellular adhesion molecule-1 (ICAM-1) and nucleolin (NCL) as important host factors, demonstrating that simultaneous suppression of both markedly reduces infection efficiency.

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Hemophilia A gene therapy: Moving to the next chapter Factors VIII and IX (FVIII and FIX) play a critical role in the blood coagulation system, amplifying thrombin generation to halt blood loss. Their congenital deficiency results in the inherited bleeding disorders hemophilia A and B, respectively.

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Cardiolipin remodeling in diabetic cardiomyopathy: Spotlight on ALCAT1 Diabetes mellitus represents a major global health burden, affecting approximately 10% of the adult population worldwide. It is among the most prevalent cardiovascular risk factors, with nearly one-third of individuals with diabetes developing diabetic cardiomyopathy (DbCM), a myocardial disease associated with an increased risk of heart failure. DbCM is defined as myocardial dysfunction occurring in the absence of other cardiovascular comorbidities, such as coronary artery disease, hypertension, or valvular heart disease.

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Advanced targets of precision epigenetic engineering and the safety of cell therapies In this issue of Molecular Therapy, Allas et al. present an investigation of the roles of JMJD3 (KDM6B) and UTX (KDM6A) in chondrogenesis and their application in gene-modified mesenchymal stem cell (MSC) therapy for cartilage tissue engineering.1 Both JMJD3 and UTX are demethylases of histone H3 at lysine 27 (H3K27) and regulate the transcriptional activation of key developmental and differentiation genes. Both JMJD3 and UTX play critical roles in removing the repressive H3K27me3 mark, thereby promoting the expression of chondrogenic transcription factors such as SOX9, COL2A1, and ACAN, which function as an epigenetic signature of MSC regulation.

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Effector CD8 T cells show additional weaponry during T cell-mediated allograft rejection The incidence of T cell-mediated graft rejection continues to be a problem in clinical transplantation, with 5%–9% of grafts continuing to be lost in the first year and an average graft survival at 5 years of only about 70%, which drops precipitously with greater time post-transplant.1,2 Acute T cell-mediated rejection (TCMR) prompts for-cause biopsies and increases in immunosuppression, and acute graft injury predisposes to the development of chronic injury, further limiting optimal graft survival.

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Directing mesothelin-targeted chimeric antigen receptor T cells to solid tumors In this issue of Molecular Therapy, Barber-Rotenberg et al. present pivotal results from a phase 1 clinical trial evaluating first-in-human mesothelin-directed chimeric antigen receptor (CAR) T cells.1 By using a fully humanized single-chain variable fragment (scFv) to treat patients with advanced-stage lung adenocarcinoma, ovarian cancer, and mesothelioma, the authors illustrate a means to transition from murine-derived constructs to a humanized CAR. Previously, two patients in the trial died after a high dose of CAR T cells (intravenous administration of 108 cells/m2).

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Cholesterol and the muscle factory: Bypassing defective LDL clearance in familial hypercholesterolemia Can skeletal muscle be repurposed as a therapeutic “factory” to treat familial hypercholesterolemia (FH)? Under normal physiology, the liver maintains circulating cholesterol homeostasis through low-density lipoprotein receptor (LDLR)-mediated clearance. In FH, however, defects in the LDLR disrupt this pathway, leading to the accumulation of LDL cholesterol in the circulation. In this issue of Molecular Therapy, Vitale and colleagues propose an unexpected redesign of this system: transforming skeletal muscle into a therapeutic factory capable of producing a circulating LDL-binding fusion protein that redirects LDL particles toward cellular uptake through an alternative receptor pathway.

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Non-Viral Targeted Integration at the CISH Locus Enables CAR-NK Cell Engineering with Enhanced Anti-Tumor Activity Wu and colleagues introduce CLICK, a non-viral strategy that integrates CARs into the CISH locus in NK cells, simultaneously disrupting a metabolic checkpoint and enabling sustained CAR expression. This dual mechanism enhances persistence and antitumor activity, supporting scalable production of next-generation allogeneic CAR-NK cell therapies.

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Single-base 2'OMe-modified LNA and MOE gapmers selectively silence ACVR1R206H in FOP, improving muscle and tendon bioavailability and safety Anwar and colleagues report a chemically optimized antisense gapmer strategy that selectively silences the pathogenic ACVR1R206H allele in fibrodysplasia ossificans progressiva, sparing the wild-type allele. The study indicates that incorporating a single-base 2′-O-methyl modification could potentially improve allele selectivity and safety of allele-selective gapmers.

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A computational model-powered platform to inform the development of GalNAc-conjugated siRNA therapeutics Yan and colleagues developed a computational model-powered, user-friendly platform for GalNAc-siRNA therapeutics. The platform was applied to facilitate the development of a novel GalNAc-siRNA, SAL0132, demonstrating the reliability and advantages of this platform in predicting drug behavior across species and accelerating clinical translation, especially for non-specialist users and clinicians.

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LINE-1 Retrotransposons: Multifaceted Functions and Regulatory Mechanisms in Health and Disease This review summarizes the physiological and pathological duality of LINE-1, outlining its transcriptional and epigenetic regulation and how LINE-1 DNA, RNA, and proteins influence development and tissue repair while driving genomic instability and inflammation in cancer and aging, highlighting LINE-1 as a promising biomarker and therapeutic target.

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ClinASO: an open-source platform for rapid drug discovery of gapmer antisense oligonucleotides ClinASO is an open-source, integrated online platform that enables rapid identification of potent, SNP-free gapmer ASOs, whose sequences are homologous to wild-type animal disease models for therapeutic validation. Across four independent disease targets, ClinASO-designed ASO sequences demonstrated potent silencing efficacy in vivo.

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CAR- T cells directed toward PD-L1 demonstrate potent, antigen-specific activity against Cholangiocarcinoma: A Proof-of-Concept Study Engineered PD-L1–targeted CAR-T cells effectively overcome immune evasion to achieve robust anti-cancer efficacy in cholangiocarcinoma. These cells showed strong, antigen-specific cytotoxicity, reduced tumor burden in vivo, and enhanced antitumor activity when combined with gemcitabine in multicellular models in vitro.

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The Good, the Bad and the Stable: Selecting Housekeeping Genes for dPCR-based RNA Quantification in NHP and Mouse Preclinical Studies Gene expression analysis is a fundamental bioanalytical readout in vitro and in vivo. Digital PCR (dPCR) is transforming the field by enabling absolute quantification through single-molecule counting. This study demonstrates that housekeeping genes as process controls are essential, and that multiplexed normalization enhances precision and reliability in preclinical models.

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Systemic clinical grade recombinant decorin reduces disease burden and fibrosis in advanced recessive dystrophic epidermolysis bullosa Gretzmeier and colleagues establish scalable production of GMP-grade recombinant human decorin (rh Decorin) and show that systemic delivery limits fibrosis in a model of advanced recessive dystrophic epidermolysis bullosa (RDEB). By accumulating in injured tissue, rh Decorin evokes matrix remodeling and inhibits cellular contractility supporting its therapeutic potential in RDEB.

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Challenging the More-Is-Better Dogma: A Precision-Optimized AAV Gene Therapy for SMA Wu and colleagues challenged the "more-is-better" paradigm in previous generations of gene therapy, and developed EXG001-307, an intra-CSF AAV9 therapy for SMA through comprehensive optimization and screening. Preclinical studies confirmed its superior efficacy and favorable safety profile, supporting its clinical advancement as a safer, targeted gene therapy.

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News from biotech

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Transient prophylactic immunosuppression with abatacept or dasatinib prevents immune responses in AAV gene transfer Immune responses to the AAV vector capsid and transgene products limit gene therapy efficacy and safety. In mouse models, transient immunosuppression with abatacept or dasatinib suppressed humoral and cellular immunity, enabling vector redosing. Abatacept showed superior efficacy, offering a promising strategy to enhance AAV gene therapy's clinical potential.

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A Single-Cell Multi-omics Assay for Simultaneous Measurement of Vector Copy Number and Protein Expression in CAR-T Cells Yang and colleagues present a single-cell multi-omics platform enabling simultaneous analysis of vector genotype, copy number, and immunophenotype in CAR T cell products. This approach advances product characterization by revealing clonal heterogeneity and transgene variability, supporting safer and more effective CAR T cell therapies.

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A molecular makeover of laminin-α4 with linker proteins to mimic the function of laminin-α2 for the treatment of LAMA2-CMD Laminin-α2-related congenital muscular dystrophy (LAMA2-CMD) is a fatal muscle disease with a world-wide prevalence estimated at 8.3 per million.1 LAMA2-CMD is caused by mutations in the LAMA2 gene resulting in the loss of laminin-α2 protein.2 Children with LAMA2-CMD present with hypotonia from birth, demyelinating neuropathy, muscle atrophy, and limited eye movement. Patients exhibit feeding problems and respiratory insufficiency, often requiring the placement of a feeding tube and ventilator assistance.

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Bringing in vivo CAR to the clinic: Promise, pitfalls, and questions to ask The prospect of shifting CAR T cell manufacturing from an in vitro to an in vivo setting has been met with much enthusiasm, given its potential to drastically reduce cost and increase access to CAR T cell therapy. However, in vivo CAR T cell therapy is still in early stages of development, and many details of vector delivery, safety, efficacy, and monitoring remain to be established. In this issue of Molecular Therapy, Lemgart et al. describe the design and pre-clinical testing of an in vivo CD22-targeted CAR T product, which is delivered to CD8+ T cells by lipid nanoparticles (LNPs).

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Messenger RNA and Guide RNA Distributions in Lipid Nanoparticles Impact Gene-editing Efficiency In Vivo Single-particle analysis of RNA payload distribution in gene editing lipid nanoparticles (LNP) reveals that RNA copies per particle and the fraction of empty particles correlate with in vivo gene editing efficacy. This study provides new quality metrics for rational LNP design and links formulation parameters to functional outcomes.

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NeuroD1 Gene Therapy Inhibits Glioma Growth and Extends Life Span through In Vivo Reprogramming Approach Chen and colleagues demonstrate that AAV-mediated NeuroD1 gene therapy reprograms glioblastoma cells towards neuronal lineage, suppressing tumor growth and extending survival in mouse models. This reprogramming strategy shows dose-dependent efficacy and synergy with temozolomide, supporting its potential as a novel treatment for GBM.

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Promoting donor microglial replacement through augmented conditioning or radiation sensitivity Lund and colleagues determined myeloid donor engraftment of the brain is enhanced with increased intensity of pre hematopoietic cell transplant conditioning. Alternatively, utilizing mice with genetic radiation sensitivity also permitted high level of donor myeloid brain engraftment due to enhanced microglial niche clearance

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First-in-human intracisternal dosing of RGX-111 in severe MPS I is well-tolerated and generates sustained neurodevelopment without HSCT Safety, biochemical, and clinical outcomes of a single-center, single-patient, open-label, first-in-human study of intra-cisterna magna RGX-111 (adeno-associated virus serotype 9-human IDUA) gene therapy in a severe mucopolysaccharidosis type I subject are reported. Six years post-dosing, the child, who has never received stem cell transplantation, demonstrates ongoing acquisition of cognitive abilities.

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