Human gene therapy最新文献

{"title":"Less Invasive Light Irradiation Methods for Inner Ear Gene Therapy Based on Photoswitch Technology: Toward Clinical Translation.","authors":"Masao Noda, Takahiro Otabe, Ryota Koshu, Naomi Takino, Mika Ito, Makoto Ito, Fuun Kawano, Takahiro Nakajima, Moritoshi Sato, Shin-Ichi Muramatsu","doi":"10.1177/10430342251415191","DOIUrl":"10.1177/10430342251415191","url":null,"abstract":"<p><p>Hearing impairment, one of the most prevalent sensory disorders, remains a major risk factor for dementia in the aging population. Although interventions such as hearing aids and cochlear implants provide partial benefit, they do not address the underlying pathology of sensorineural hearing loss. Inner ear gene therapy has attracted significant attention as a promising approach; however, its clinical translation requires minimally invasive and controllable methods for gene activation. We previously developed a photoactivatable Cre recombinase (PA-Cre) system for spatiotemporal regulation of gene expression. In this study, we evaluated the feasibility of irradiating the external auditory canal (EAC) and tympanic membrane (TM) as minimally invasive approaches for activating cochlear gene expression. Tyrosine-mutant AAV9/3 vectors (AAV.GTX) encoding PA-Cre and a Cre-dependent reporter (sfGFP-to-tdTomato) were injected via the round window membrane in 9-week-old C57BL/6J mice. Seven days later, light irradiation was applied using three approaches: (1) Direct cochlear irradiation via postauricular access, (2) TM irradiation with a fiber-optic probe, and (3) noninvasive EAC irradiation through the intact TM. Recombination efficiency in inner hair cells (IHCs) was quantified using whole-mount immunohistochemistry. AAV.GTX efficiently transduced IHCs and drove robust sfGFP expression. In the absence of light, tdTomato expression remained minimal (<5%), indicating low basal Cre leak activity. Direct cochlear irradiation produced strong recombination (conversion rate: 88.4 ± 1.5%), confirming the functionality of PA-Cre in the mouse inner ear. TM and EAC irradiation yielded high conversion efficiencies (95.8 ± 1.7% and 97.6 ± 1.2%, respectively), comparable to direct irradiation, while preserving cochlear integrity. These findings indicate that PA-Cre functions effectively in the mouse cochlea with minimal leak activity and that TM and EAC irradiation enable robust, minimally invasive gene activation. This strategy highlights the light-mediated, noninvasive modulation of cochlear gene expression, informing future translational development.</p>","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":"341-348"},"PeriodicalIF":4.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146112839","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lipid Nanoparticle-Delivered mRNA Therapy Corrects Neonatal Murine MPS I-H.","authors":"Jiamei Fu, Mei Luo, Xiu Jin, Jing Su, Li Song, Qiuxia Xu, Fanfei Liu, Xiaoyi Wu, Min Luo, Qin Ye, Qiqi Li, Yifang An, Chengda Ren, Ming Hu, Man Liu, Manjun Li, Shaohua Yao, Yang Yang","doi":"10.1177/10430342251412392","DOIUrl":"https://doi.org/10.1177/10430342251412392","url":null,"abstract":"<p><p>Mucopolysaccharidosis type I-Hurler (MPS I-H) is a severe lysosomal storage disorder caused by α-L-iduronidase (IDUA) deficiency, leading to glycosaminoglycan (GAG) accumulation and progressive multisystem dysfunction, including the central nervous system (CNS). Early hematopoietic stem cell transplantation remains the primary disease-modifying intervention for MPS I-H despite its clinical challenges. Conventional enzyme replacement therapy (ERT), which has limited CNS efficacy due to blood-brain barrier (BBB) restrictions, is being addressed by the development of novel BBB-penetrating ERT platforms. Recently, mRNA therapy has become a promising treatment option for rare genetic diseases by enabling the <i>in vivo</i> supplementation of defective or deficient proteins to ameliorate the disease phenotype. To evaluate mRNA therapy for MPS I-H, we screened ionizable lipids to develop lipid nanoparticle systems optimized for hepatic delivery, which were subsequently used to encapsulate mRNA encoding human IDUA (hIDUA) fused to a validated BBB-penetrating melanotransferrin peptide (MTfp). This formulation was intravenously administered to neonatal MPS I-H mice at a dose of 1.0 mg/kg every 2 weeks for 4 months. The treatment significantly increased IDUA enzyme activity in both the serum and liver. Concurrently, it reduced GAG accumulation in the urine, peripheral tissues, and partial CNS regions (olfactory bulbs, hippocampus, and cerebellum). Furthermore, the treatment significantly improved cardiac and skeletal development, as assessed by echocardiography and micro-computed tomography, respectively. Notably, it also enhanced cognitive function, as evidenced by the improved performance in the Delayed-Matching-to-Place dry maze test. Our findings demonstrate that LNP-MTfp-hIDUA treatment effectively ameliorates key pathological features and promotes neurodevelopment in MPS I-H, establishing a promising and safe therapeutic strategy for this disorder.</p>","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":"37 7-8","pages":"311-328"},"PeriodicalIF":4.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147511854","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An Analysis of Biomarkers for the Evaluation of Gene Therapy in Niemann-Pick Disease Type C1 Mice.","authors":"Chika Watanabe, Masamitsu Maekawa, Eriko Jimbo, Yoshie Kurokawa, Karin Kojima, Kazuhiro Muramatsu, Keitaro Miyoshi, Chen Wu, Miki Igarashi, Shin-Ichi Muramatsu, Hitoshi Osaka, Yoshikatsu Eto, Takanori Yamagata","doi":"10.1177/10430342251412391","DOIUrl":"https://doi.org/10.1177/10430342251412391","url":null,"abstract":"<p><p>Niemann-Pick disease type C1 (NPC1) is an autosomal recessive lysosomal storage disorder caused by pathogenic variants of the <i>NPC1</i> gene that encodes a protein essential for lysosomal cholesterol transport. A deficiency in NPC1 results in the accumulation of unesterified cholesterol and sphingolipids, leading to neurological, psychiatric, and hepatic manifestations from infancy to adulthood. The currently approved treatment is palliative. Although the efficacy of gene therapy has been demonstrated in murine models, reliable biomarkers for evaluating the treatment effects remain unknown. We evaluated adeno-associated virus (AAV) vector-mediated NPC1 gene therapy in <i>Npc1</i> homo-knockout (<i>Npc1^-/-</i>) mice, focusing on blood-based biomarkers. An AAV vector carrying human <i>NPC1</i> under a cytomegalovirus promoter (AAV-<i>hNPC1</i>) was administered intraperitoneally on days 6-8 after birth at varying vector doses and analyzed at multiple time points: 1.8 × 10¹¹ vector genomes/mouse analyzed at 7 weeks (Low/7w) and 1.0 × 10¹² vector genomes/mouse at 4 weeks (High/4w) and 9 weeks (High/9w). <i>hNPC1</i> is expressed in the brain and liver, and a degree of neuronal cell survival is observed. High-dose AAV treatment improves body weight and rotarod performance. Plasma <i>N</i>-palmitoyl-<i>O</i>-phosphocholine-serine (PPCS) and lysosphingomyelin (lyso-SM) levels were significantly elevated in <i>Npc1^-/-</i> mice. PPCS increased with disease progression but was significantly decreased after later points of high-dose AAV treatment (saline-treated <i>Npc1^-/-</i> mice: 12.88 ± 3.53 ng/mL, AAV-treated <i>Npc1^-/-</i> mice: 7.87 ± 1.67 ng/mL, <i>p</i> = 0.0008). Lyso-SM and oxysterols showed limited changes after therapy. Vector genome analysis revealed higher and more sustained levels in the brain than in the liver, which is consistent with rapid hepatocyte proliferation-reducing vector persistence. These findings demonstrate that systemic AAV-<i>hNPC1</i> therapy ameliorates motor and neurological deficits but has a limited impact on several cholesterol-related biomarkers. PPCS has been suggested as a sensitive biomarker of therapeutic response and warrants further evaluations in preclinical and clinical NPC1 gene therapy trials.</p>","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":"37 7-8","pages":"300-310"},"PeriodicalIF":4.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147511811","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring Development Options of a Polishing Chromatography Step for AAV7 and AAV8.","authors":"Xiaotong Fu, Colin Haws, Darren Begley, Richard Gyamfi Atta","doi":"10.1177/10430342251408498","DOIUrl":"10.1177/10430342251408498","url":null,"abstract":"<p><p>As impact of adeno-associated virus (AAV) empty capsids on drug product safety and quality remains inconclusive, downstream purification strategy has been focusing on empty capsid removal. Anion-exchange chromatography (AEX) has made significant progress in separating empty from full capsids in recent years. Still, achieving baseline resolution between different AAV subpopulations remains challenging due to subtle charge differences. With a certain AAV construct design, this difficulty is compounded when upstream packaging efficiency is low or when empty and full capsids of a particular serotype have similar electrostatic charge profiles. To improve separation and product purity, secondary interaction mechanisms using multimodal (mix-mode) chromatography are often introduced.In this study, we present a case study on developing a polishing chromatography step to remove empty capsids from AAV7 and AAV8 preparations. To create a challenging feed material for the polishing step, we used small gene-of-interest (GOI) and poorly packaged starting materials. We investigated multiple critical process parameters, including buffer matrix, salt concentration, pH, peak fractionation strategies, and column chemistry (strong AEX vs. mix-mode). Mass photometry (MP) and charge detection mass spectrometry (CDMS) were used to characterize capsid populations. Optimized AEX conditions for AAV8 achieved 80% full capsids by MP and 90% GOI-containing capsids by CDMS. For AAV7, the mix-mode column demonstrated improved resolution compared with the standard AEX gradient method. These results demonstrate that mix-mode chromatography provides an alternative polishing option for serotypes where traditional AEX fails to achieve the desired separation.</p>","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":"372-382"},"PeriodicalIF":4.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145855742","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Quantification of Linear Polyethylenimines in Recombinant Adeno-Associated Virus by High-Performance Liquid Chromatography with Charged Aerosol Detection.","authors":"Amelia W Paine, Stacey Nash, Nicolsond Nelson, Eric Crain, Xiaohui Lu, James Warren, Jin Seon Park","doi":"10.1177/10430342251411041","DOIUrl":"10.1177/10430342251411041","url":null,"abstract":"<p><p>Polyethylenimine (PEI) is widely employed as a transfection reagent in recombinant adeno-associated virus (rAAV) manufacturing, but it must be removed from the final product due to its potential toxicity. Accurate quantification of PEI in complex biological matrices such as rAAVs is challenging, largely because the strong electrostatic attraction between PEI and nucleic acids can hinder the accuracy of its quantification. Here, we report a robust high-performance liquid chromatography method with charged aerosol detection for the quantification of residual linear PEI in purified AAV samples. Sample preparation includes treatment with trifluoroacetic acid and hydrochloric acid at 60°C to denature capsid protein, disrupt PEI-DNA polyplexes, and hydrolyze nucleic acids. The method achieves a limit of detection of 5 µg/mL and a limit of quantitation of 10 µg/mL in spike-and-recovery studies, with quantification confirmed via visual peak identification. This approach enables sensitive, specific, and reproducible PEI measurement and provides a valuable tool for process monitoring and quality control in gene therapy manufacturing.</p>","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":"365-371"},"PeriodicalIF":4.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146131664","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"AAV Vectors Have Limited Impact on Host Chromatin Accessibility and Nuclear Architecture.","authors":"Joël W Zöllig, Maija K Pietilä, Melina O Bräuer, Kurt Tobler, Cornel Fraefel","doi":"10.1177/10430342261437975","DOIUrl":"https://doi.org/10.1177/10430342261437975","url":null,"abstract":"<p><p>Recombinant adeno-associated virus (rAAV) vectors are widely used for gene therapeutics, yet their early effects on host chromatin remodeling and nuclear organization remain insufficiently characterized. In contrast, several DNA viruses are known to remodel host chromatin accessibility, for example, Herpes simplex virus type 1 (HSV-1) in mammalian cells and baculoviruses in insect systems. Here, we evaluated genome accessibility and nuclear organization of primary human fibroblast cells at 24 and 48 h after infection with wild-type AAV2, single-stranded (ss) and self-complementary rAAV2, as well as ssAAV2 and ssAAV-DJ in human lung carcinoma cells. Genome-wide assay for transposase-accessible chromatin using sequencing showed no detectable change in host chromatin accessibility at either time point. A DNase I digestion assay at five candidate loci supported this observation. Although host accessibility remained stable, immunofluorescence-based single-cell analyses uncovered modest changes in histone abundance, RNA polymerase II-associated signals, nuclear morphology, and the organization of liquid-liquid phase-separated nuclear compartments. These effects were generally mild in primary fibroblasts but showed greater dependence on vector type, cell cycle state, and transgene expression in carcinoma cells. Collectively, at the tested doses and times, AAV-based vectors did not remodel chromatin accessibility at scale and induced only small changes in polymerase-associated readouts and nuclear architecture. These data are consistent with limited nuclear perturbation under these conditions.</p>","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":"10430342261437975"},"PeriodicalIF":4.0,"publicationDate":"2026-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147580221","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Biodistribution of AAV-TT and AAV9 in the Nonhuman Primate Brain.","authors":"Alberto J Rico, Nelly Jolinon, Teresa Torre-Muruzabal, R Michael Linden, Els Henckaerts, José L Lanciego","doi":"10.1177/10430342261427733","DOIUrl":"https://doi.org/10.1177/10430342261427733","url":null,"abstract":"<p><p>The adeno-associated virus (AAV) capsid variant known as \"true type\" (AAV-TT) is a capsid with enhanced central nervous system tropism and efficient retrograde transport across brain circuits. This property enables AAV-TT to transduce neurons in multiple regions projecting to the site of injection, as previously shown in rodent and sheep models. Such spreading offers the potential for broad therapeutic vector distribution to functionally connected brain areas via a single intraparenchymal administration. To assess the clinical potential of AAV-TT, we delivered a green fluorescent protein (GFP)-expressing AAV-TT vector into the left commissural putamen of two young adult <i>Macaca fascicularis</i>. For comparison, two additional animals received AAV9-GFP. Four weeks post-injection, animals were euthanized, and whole-brain transduction patterns were analyzed using a dedicated Aiforia^® deep learning-based image analysis algorithm to quantify GFP+ neurons. We observed GFP expression in structures known to innervate the injection site, consistent with retrograde transport. Both AAV-TT and AAV9 showed similar overall distribution patterns, but AAV-TT demonstrated modestly enhanced neuronal transduction efficiency compared with AAV9. This study provides the first direct comparison of AAV-TT and AAV9 in the adult nonhuman primate brain and positions AAV-TT as a promising tool for disease modeling and therapeutic interventions in neurodegenerative disorders targeting anatomically distributed neural circuits.</p>","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":"10430342261427733"},"PeriodicalIF":4.0,"publicationDate":"2026-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147377186","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Brain-Directed AAV Gene Therapy Rescues a Mouse Model of the CLN5 Form of Neuronal Ceroid Lipofuscinosis Disease and Normalizes a Blood Plasma Biomarker of Neurodegeneration.","authors":"Wenfei Liu, Amy F Geard, Giulia Massaro, Michael P Hughes, Mikel Aristorena, Oliver Coombe-Tennant, Liangyuan Xu, Olha Semenyuk, Reuben Bush, Danielle Te Vruchte, David Priestman, Rhiannon Laban, Elena Veleva, Amanda J Heslegrave, Henrik Zetterberg, Frances M Platt, Alexander J Smith, Sara E Mole, Robin R Ali, Ahad A Rahim","doi":"10.1177/10430342251403448","DOIUrl":"10.1177/10430342251403448","url":null,"abstract":"<p><p>CLN5 disease, caused by mutations in the <i>CLN5</i> gene, is a form of neuronal ceroid lipofuscinoses (Batten disease). Patients suffer progressive motor dysfunction, vision loss, seizures, and dementia, leading to premature death. Here, we report a preclinical study of AAV9-mediated gene therapy in a <i>Cln5</i>^-/- mouse model. Single-dose AAV9 carrying human <i>CLN5</i> driven by the CAG or human synapsin 1 promoter (hSYN) was administered via intracerebroventricular injection into neonatal and juvenile <i>Cln5</i>^-/- mice. Treatment efficacy was evaluated by assessment of neurodegeneration, neuroinflammation, locomotor function, and survival. AAV9 expressing <i>CLN5</i> driven by the hSYN promoter significantly alleviated neurodegeneration, improved biochemical and glycosphingolipid profiles, neuropathological and locomotor function, and extended lifespan of the <i>Cln5</i>^-/- mice. However, gene transfer employing the CAG promoter demonstrated limited therapeutic efficacy. Furthermore, delayed intervention in juveniles provided superior therapeutic response compared with early neonatal intervention and normalized lifespan. Finally, blood plasma neurofilament light that is significantly elevated in the <i>Cln5</i>^-/- mice is restored to normal wildtype levels following treatment. These results indicate that brain-directed adeno-associated virus (AAV) gene therapy could be a promising treatment strategy for CLN5 disease and efficacy might be monitored using a noninvasive blood plasma biomarker.</p>","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":"241-261"},"PeriodicalIF":4.0,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145850108","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Maximizing Access to Cell and Gene Therapy for Patients with Rare Diseases.","authors":"Terence R Flotte, Guangping Gao","doi":"10.1177/10430342261422716","DOIUrl":"10.1177/10430342261422716","url":null,"abstract":"","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":"163-164"},"PeriodicalIF":4.0,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146118890","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Learnings from Patient Mortality after Delandistrogene Moxeparvovec Administration: A Report of Two Cases and Expert Committee Considerations for Future Mitigation and Management.","authors":"Perry B Shieh, Crystal Proud, Tamir Diamond, Catherine A Chapin, Jawad Ahmad, Alan D Salama, Carsten G Bönnemann, Jonathan Soslow, Barry J Byrne, Aravindhan Veerapandiyan, John F Brandsema, Susan Matesanz, Benjamin J Samelson-Jones, Benjamin J Wilkins, Marianne Gerber, Kara E Godwin Wild, Stefanie Mason, Damon Asher, Craig M McDonald, Jerry R Mendell","doi":"10.1177/10430342261423168","DOIUrl":"10.1177/10430342261423168","url":null,"abstract":"<p><p>Acute liver injury (ALI) is a recognized adverse event with adeno-associated virus (AAV)-based gene therapies, including delandistrogene moxeparvovec, an AAVrh74-based gene therapy for Duchenne muscular dystrophy. Progression of ALI to acute liver failure (ALF) is rare. In clinical trials, ALF was defined as an international normalized ratio ≥1.5 with encephalopathy and/or ascites, occurring <26 weeks since product/treatment exposure, and in the absence of identified preexisting liver disease as assessed by the treating investigator. The two cases presented here represent the only known instances of ALF following delandistrogene moxeparvovec to date, both resulting in fatal outcomes. Both cases occurred in nonambulatory patients (ages 15 and 16 years). Both patients exhibited abrupt elevations in aminotransferases from baseline approximately 4 weeks after delandistrogene moxeparvovec administration. Over the subsequent weeks and despite interventions, aminotransferases, including gamma-glutamyl transferase (GGT), declined concurrently with a continued rise in total bilirubin, consistent with severe hepatocellular injury and a harbinger of ALF. An interdisciplinary expert panel was convened and concluded that no single biomarker or clinical feature consistently predicted the rapid progression of severe ALI to ALF. Advisors recommended basing treatment intervention for severe ALI on the rate and magnitude of changes from baseline in liver biomarkers (<i>e.g.,</i> 2-3× increase in alanine aminotransferase within ≤1 week). For these severe cases, most advisors recommended intravenous methylprednisolone as the initial treatment whereas typical ALI may be managed with oral corticosteroid adjustment or may resolve with time, as seen in the clinical trial experience. Advisors hypothesized that delandistrogene moxeparvovec-related ALI is T-cell-mediated and discussed the potential of additional immunosuppression. Advisors also recommended enhancing baseline evaluation for hepatic comorbidities with lipid profiling, transient elastography, and abdominal ultrasound to further study potential risk factors for ALI progressing to ALF. Finally, there was strong support for generating additional real-world evidence and conducting prospective clinical trials to inform clinical management of ALI in practice.</p>","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":"262-279"},"PeriodicalIF":4.0,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146179456","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}