Human gene therapy最新文献

{"title":"Thrombotic Microangiopathy Associated with Systemic Adeno-Associated Virus Gene Transfer: Review of Reported Cases.","authors":"Genevieve A Laforet","doi":"10.1089/hum.2024.156","DOIUrl":"https://doi.org/10.1089/hum.2024.156","url":null,"abstract":"<p><p>Complement-mediated thrombotic microangiopathy (TMA) in the form of atypical hemolytic uremic syndrome (aHUS) has emerged as an immune complication of systemic adeno-associated virus (AAV) gene transfer that was unforeseen based on nonclinical studies. Understanding this phenomenon in the clinical setting has been limited by incomplete data and a lack of uniform diagnostic and reporting criteria. While apparently rare based on available information, AAV-associated TMA/aHUS can pose a substantial risk to patients including one published fatality. Reported cases were originally limited to pediatric Duchenne muscular dystrophy patients receiving micro- or mini-dystrophin transgenes via AAV9 but have subsequently been reported in both pediatric and adult patients across a range of disorders, transgenes, promoters, and AAV capsid types. This article provides an introduction to the complement system, TMA and aHUS, and anticomplement therapies, then presents clinical reviews of AAV-associated TMA/aHUS cases that have been reported publicly. Finally, exploration of risk factors and current and future mitigation approaches are discussed.</p>","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143004525","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":"Novel Cystic Fibrosis Ferret Model Enables Visualization of CFTR Expression Cells and Genetic CFTR Reactivation.","authors":"Feng Yuan, Xingshen Sun, Soo Yeun Park, Yinghua Tang, Zehua Feng, Mehrnoosh Ebadi, Yaling Yi, Adriane E Thompson, Joseph D Karippaparambil, John F Engelhardt, Ziying Yan","doi":"10.1089/hum.2024.215","DOIUrl":"https://doi.org/10.1089/hum.2024.215","url":null,"abstract":"<p><p>Cystic fibrosis (CF) is caused by mutations in the <i>cystic fibrosis transmembrane conductance regulator</i> (<i>CFTR</i>). While gene therapy holds promise as a cure, the cell-type-specific heterogeneity of <i>CFTR</i> expression in the lung presents significant challenges. Current CF ferret models closely replicate the human disease phenotype but have limitations in studying functional complementation through cell-type-specific CFTR restoration. To address this, we developed a new transgenic ferret line, <i>CFTR</i>^{int1-eGFP(lsl)}, in which a Cre-recombinase (Cre)-excisable enhanced fluorescent protein (eGFP) reporter cassette is knocked in (KI) to intron 1 of the <i>CFTR</i> locus. Breeding this reporter line with <i>CFTR</i>^G551D CF ferret resulted in a novel CF model, <i>CFTR</i>^{int1-eGFP(lsl)/G551D}, with disease onset manageable via the administration of CFTR modulator VX770. In this study, we confirmed two key properties of the <i>CFTR</i>^{int1-eGFP(lsl)/G551D} CF ferrets: (1) cell-type-specific expression of the CFTR(N-24)-eGFP fusion protein, driven by the intrinsic <i>CFTR</i> promoter, in polarized epithelial cultures and selected tissues, and (2) functional reversion of the KI allele via Cre-mediated excision of the reporter cassette. This model provides a valuable tool for studying the effects of targeted CFTR reactivation in a cell-type-specific manner, which is crucial for enhancing our understanding of CFTR's roles in modulating airway clearance and innate immunity, and for identifying relevant cellular targets for CF gene therapy.</p>","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142947972","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":"The 2024 Nobel Prize: Impact of the Discovery of miRNA on the Field of Gene Therapy.","authors":"Christian Mueller, Guangping Gao, Terence R Flotte","doi":"10.1089/hum.2024.98457","DOIUrl":"https://doi.org/10.1089/hum.2024.98457","url":null,"abstract":"","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142921531","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":"Vectorized Human Antibody-Mediated Anti-Eosinophil Gene Therapy.","authors":"Maria Gioulvanidou, Selenay Sarklioglu, Xinlei Chen, Irina V Lebedeva, Yeliz Inalman, Mary Ann Pohl, Lloyd Bourne, David Andrew, Ivo C Lorenz, Katie M Stiles, Odelya E Pagovich, Neil R Hackett, Stephen M Kaminsky, Miguel de Mulder Rougvie, Ronald G Crystal","doi":"10.1089/hum.2024.165","DOIUrl":"https://doi.org/10.1089/hum.2024.165","url":null,"abstract":"<p><p>Chronic hypereosinophilia, defined as persistent elevated blood levels of eosinophils ≥1,500/μL, is associated with tissue infiltration of eosinophils and consequent organ damage by eosinophil release of toxic mediators. The current therapies for chronic hypereosinophilia have limited success, require repetitive administration, and are associated with a variety of adverse effects. As a novel approach to treat chronic hypereosinophilia, we hypothesized that adeno-associated virus (AAV)-mediated delivery of an anti-human eosinophil antibody would provide one-time therapy that would mediate persistent suppression of blood eosinophil levels. To assess this hypothesis, we first generated a human monoclonal antibody (mAb) directed against Siglec8, a sialic-acid binding immunoglobulin-like lectin, expressed at high levels on the cell surface of human eosinophils. Transgenic mice with a human immunoglobulin repertoire were immunized with human Siglec8 protein or DNA encoding human Siglec8. Based on target binding assessments, the 08C07 mAb was chosen for further study. The human variable regions of 08C07 were joined to the human Ig constant region, creating H08C07 (hAntiEos), a fully human anti-human eosinophil mAb. Using the gene sequence of hAntiEos, we created AAVrh.10hAntiEos, an AAVrh.10-based vector expressing the heavy and light chains of H08C07. Intravenous administration of AAVrh.10hAntiEos (10¹¹ genome copies or gc) to C57Bl/6 mice resulted in persistent elevated serum levels of hAntiEos. <i>In vivo</i> gene therapy generated hAntiEos bound to recombinant human Siglec8 protein in a dose-dependent manner and to human eosinophils, mediated apoptosis of human eosinophils, and antibody-dependent cellular cytotoxicity activity against human eosinophils. Consistent with these data, administration of AAVrh.10hAntiEos to human CD34⁺ transplanted NSG-SGM3 immunodeficient mice suppressed levels of human eosinophils <i>in vivo</i>. AAVrh.10hAntiEos holds the potential to offer therapeutic benefit to patients with chronic hypereosinophilia.</p>","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142894035","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":"Intracisternal AAV9-MAG-<i>hABCD1</i> Vector Reverses Motor Deficits in Adult Adrenomyeloneuropathy Mice.","authors":"Yasemin Özgür Günes, Catherine Le Stunff, Pierre Bougnères","doi":"10.1089/hum.2024.175","DOIUrl":"https://doi.org/10.1089/hum.2024.175","url":null,"abstract":"<p><p>Worldwide, thousands of male patients who carry ATP Binding Cassette Subfamily D Member 1 (<i>ABCD1</i>) mutations develop adrenomyeloneuropathy (AMN) in mid-adulthood, a debilitating axonopathy of the spinal cord. Today AAV gene therapy brings the most hope for this orphan disease. We previously reported that an AAV9-MAG-<i>hABCD1</i> vector injected intravenously in the neonatal period prevented the disease in 2-year-old <i>Abcd1-/-</i> mice, the AMN mouse model. In the current study, the same vector was injected intracisternally at 18 months of age, when about half of <i>Abcd1-/-</i> mice start losing balance and motricity. As soon as 1-3 months after vector injection, motor tests have evolved differently in treated and untreated (UT) mice. Six months after vector, treated mice (<i>n</i> = 24) had near-normal motor performances, whereas neurological state had deteriorated in UT mice (<i>n</i> = 34). In five white matter regions of the cervical spinal cord, <i>hABCD1</i> expression at 24 months of age was present in 22% (18-27) of oligodendrocytes (OLs) and 22% (17-26) of astrocytes and not detected in neurons or microglia. Abundant <i>hABCD1</i> expression was also observed in OLs and astrocytes in the cerebellum and brainstem and, to a lesser level, in the lower spinal cord, not in the dorsal root ganglia or brain cortex. In conclusion, the effect of the AAV9-MAG-<i>hABCD1</i> vector at an early symptomatic stage of the <i>Abcd1-/-</i> mouse model paves a new oligotropic way for the gene therapy of AMN.</p>","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142894034","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":"Current and Emerging Issues in Adeno-Associated Virus Vector-Mediated Liver-Directed Gene Therapy.","authors":"Pasquale Piccolo, Nicola Brunetti-Pierri","doi":"10.1089/hum.2024.179","DOIUrl":"https://doi.org/10.1089/hum.2024.179","url":null,"abstract":"<p><p>Adeno-associated virus (AAV) vectors have demonstrated safety and efficacy for gene transfer to hepatocytes in preclinical models, in various clinical trials and from a clinical experience with a growing number of approved gene therapy products. Although the exact duration is unknown, the expression of therapeutic genes in hepatocytes remains stable for several years after a single administration of the vector at clinically relevant doses in adult patients with hemophilia and other inherited metabolic disorders. However, clinical applications, especially for diseases requiring high AAV vector doses by intravenous administrations, have raised several concerns. These include the high prevalence of pre-existing immunity against the vector capsid, activation of the complement and the innate immunity with serious life-threatening complications, elevation of liver transaminases, liver growth associated with loss of transgene expression, underlying conditions negatively affecting AAV vector safety and efficacy. Despite these issues, the field is rapidly advancing with a better understanding of vector-host interactions and the development of new strategies to improve liver-directed gene therapy. This review provides an overview of the current and emerging challenges for AAV-mediated liver-directed gene therapy.</p>","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2024-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142881887","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":"Adeno-Associated Virus Gene Transfer Ameliorates Progression of Skeletal Lesions in Mucopolysaccharidosis IVA Mice.","authors":"Angélica María Herreño-Pachón, Kazuki Sawamoto, Molly Stapleton, Shaukat Khan, Matthew Piechnik, Jose Victor Álvarez, Shunji Tomatsu","doi":"10.1089/hum.2024.096","DOIUrl":"10.1089/hum.2024.096","url":null,"abstract":"<p><p>Mucopolysaccharidosis type IVA (MPS IVA) is an autosomal congenital metabolic lysosomal disease caused by a deficiency of the <i>N</i>-acetyl-galactosamine-6-sulfate sulfatase (GALNS) gene, leading to severe skeletal dysplasia. The available therapeutics for patients with MPS IVA, enzyme replacement therapy and hematopoietic stem cell transplantation, revealed limitations in the impact of skeletal lesions. Our previous study, a significant leap forward in MPS IVA research, showed that liver-targeted adeno-associated virus (AAV) gene transfer of human GALNS (hGALNS) restored GALNS enzymatic activity in blood and multiple tissues and partially improved the aberrant accumulation of storage materials. This promising approach was further validated in our current study, where we delivered AAV8 vectors expressing hGALNS, under the control of a liver-specific or ubiquitous promoter, into MPS IVA murine disease models. The results were highly encouraging, with both AAV8 vectors leading to supraphysiological enzymatic activity in plasma and improved cytoplasmic vacuolization of chondrocytes in bone lesions of MPS IVA mice. Notably, the ubiquitous promoter constructs, a potential game-changer, resulted in significantly greater enzyme activity levels in bone and improved pathological findings of cartilage lesions in these mice than in a liver-specific one during the 12-week monitoring period, reinforcing the positive outcomes of our research in MPS IVA treatment.</p>","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":"955-968"},"PeriodicalIF":3.9,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11659441/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142499368","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Focused Ultrasounds as an Adeno-Associated Virus Gene Therapy-Empowering Tool in Juvenile Mice via Intracerebroventricular Administration.","authors":"Alessandro Zappala, Heng Li, Ken Inoue","doi":"10.1089/hum.2024.108","DOIUrl":"10.1089/hum.2024.108","url":null,"abstract":"<p><p>Systemic delivery of adeno-associated virus (AAV) vectors targeting the central nervous system has the potential to solve many neurodevelopmental disorders, yet it is made difficult by the filtering effect of the blood-brain barrier and systemic complications. To overcome this limitation, we attempted to inject a Venus-expressing, oligodendrocyte-selective AAV9 viral vector in the ventricles together with lipid microbubbles and subjected them to focused ultrasound (FUS); the resulting mechanical stimulation on the brain ventricles is able to open small, temporary gaps from which vector particles can leak and spread. Our findings indicate that FUS can increase viral vector diffusion across both the anteroposterior and left-right axes without influencing cell tropism; significant effects were found with 60 and 90 s exposure time, but no effects were observed with longer intervals. Taken together, these results highlight a new strategy for the safe and effective delivery of viral vectors and offer new perspectives for the development and application of gene therapies for central nervous system diseases.</p>","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":"989-999"},"PeriodicalIF":3.9,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11659451/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142710027","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Long-Term Survival and Myocardial Function Following Systemic Delivery of Delandistrogene Moxeparvovec in DMD^MDX Rats.","authors":"Stephen Baine, Chris Wier, Luke Lemmerman, Grace Cooper-Olson, Amber Kempton, Alex Haile, Julian Endres, Alessandra Fedoce, Ellyn Nesbit, Louise R Rodino-Klapac, Rachael A Potter","doi":"10.1089/hum.2024.013","DOIUrl":"10.1089/hum.2024.013","url":null,"abstract":"<p><p>Delandistrogene moxeparvovec is a gene transfer therapy for Duchenne muscular dystrophy (DMD) that uses an adeno-associated viral vector to deliver a micro-dystrophin transgene to skeletal and cardiac muscle. This study evaluated the long-term survival and cardiac efficacy of delandistrogene moxeparvovec in a DMD-mutated (DMD^MDX) rat model of DMD-related cardiomyopathy. DMD^MDX male rats, aged 21-42 days, were injected with 1.33 × 10¹⁴ viral genomes/kilogram (vg/kg) delandistrogene moxeparvovec and followed for 12, 24, and 52 weeks. Ambulation was recorded <i>via</i> the Photobeam Activity System, whereas echocardiograms, cardiomyocyte contractility, calcium handling, and histological analysis of fibrosis were used to evaluate cardiac disease at 12-, 24-, and 52-weeks post-treatment. A separate cohort of rats was used to assess the impact of delandistrogene moxeparvovec on survival. Treatment with delandistrogene moxeparvovec extended median survival in DMD^MDX rats to >25 months versus the 13-month median survival in saline-control-treated DMD^MDX rats. Compared with saline control, delandistrogene moxeparvovec therapy elicited statistically significant improvements across cardiac parameters approaching wild-type values with additional benefits in mobility, histopathology, and fibrosis observed. Transgene expression was maintained up to >25 months and micro-dystrophin expression was broadly distributed across skeletal and cardiac muscle. Taken together, these findings demonstrate long-term cardiac efficacy and improved survival following delandistrogene moxeparvovec treatment in DMD^MDX rats.</p>","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":"978-988"},"PeriodicalIF":3.9,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11659437/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142750780","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prevalence of Neutralizing Antibodies Against AAV Serotypes 2 and 9 in Healthy Participants from Multiple Centers Across China and Patients with DMD/BMD.","authors":"Xuzhen Qin, Huan Li, Huiying Zhao, Kuanhui Xiang, Shihui Liu, Ruolin Lou, Peng Liu, Yi Dai, Chuanxin Wang, Shuyang Zhang","doi":"10.1089/hum.2024.079","DOIUrl":"10.1089/hum.2024.079","url":null,"abstract":"<p><p>To facilitate adeno-associated virus (AAV)-mediated gene therapy in China, we conducted a study on the distribution of AAV-neutralizing antibodies (NAbs) in healthy subjects and in patients with Duchenne muscular dystrophy (DMD)/Becker muscular dystrophy (BMD). A total of 352 healthy adult controls (ACs) from a national multicenter study, 100 schoolchild controls (SCs), and 281 patients with DMD/BMD from Peking Union Medical College Hospital were enrolled in this study. Cell-based inhibition assays were applied, and serum samples demonstrating 50% inhibition of infection were considered positive. The seroprevalence of AAV2 and AAV9 NAbs among the 733 participants was 86.1% and 56.3%, respectively. The AAV2 NAbs and AAV9 NAbs positivity rates in the AC, SC, and DMD/BMD groups were 97.4%/86.6%, 100.0%/17.0%, and 66.9%/32.4%, respectively. The seroprevalence of AAV NAbs gradually increased with age, especially in AAV9 NAbs. Females tended to have higher positivity rate than males. Over 85% of ACs had overlapping AAV9 and AAV2 infection. However, being positive for only AAV2 NAbs in the SC group was common, and 30.6% of patients with DMD/BMD were negative for both AAV2 and AAV9 NAbs. Our findings reveal that a significant proportion of patients with DMD/BMD were negative for AAV2 and AAV9 NAbs, which is the population that is most amenable to being treated with gene therapy.</p>","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":"969-977"},"PeriodicalIF":3.9,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11659434/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142739482","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}