Human gene therapy最新文献

{"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":"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":"77-87"},"PeriodicalIF":3.9,"publicationDate":"2025-02-01","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":"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":"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":"88-100"},"PeriodicalIF":3.9,"publicationDate":"2025-02-01","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":"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":"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":"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}

{"title":"Patient Dies in Beam Trial of Sickle Cell Disease Candidate; Company Cites Conditioning.","authors":"Alex Philippidis","doi":"10.1089/hum.2024.111924","DOIUrl":"10.1089/hum.2024.111924","url":null,"abstract":"","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":"35 23-24","pages":"951-954"},"PeriodicalIF":3.9,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11659430/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142822026","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":"Cyclosporin H Improves the Transduction of CD34⁺ Cells with an Anti-Sickling Globin Vector, a Possible Therapeutic Approach for Sickle Cell Disease.","authors":"Mirella Mormin, Luc Rigonnot, Anne Chalumeau, Annarita Miccio, Clémence Fournier, Sandya Pajanissamy, Marie Dewannieux, Anne Galy","doi":"10.1089/hum.2024.098","DOIUrl":"10.1089/hum.2024.098","url":null,"abstract":"<p><p>Sickle cell disease (SCD) is a debilitating monogenic disease originating from mutations in the hemoglobin beta chain gene producing an abnormal hemoglobin HbS. The polymerization of HbS is responsible for the sickling of erythrocytes leading to anemia and vaso-occlusive events. Gene therapy is a promising treatment of SCD, and two different gene therapy drugs, using gene editing or gene transfer, have already reached the marketing stage. There is still a need to improve the efficacy of gene therapy in SCD, particularly when using anti-sickling beta-globin gene transfer strategies, which must outcompete the pathological HbS. One possibility is to increase transduction by inhibiting lentiviral restriction factors such as interferon-induced transmembrane proteins (IFITMs). This can be achieved by the addition of cyclosporin H (CsH) during the transduction process. This strategy was applied here in CD34⁺ hematopoietic progenitor and stem cells obtained from cord blood (CB). A first series of experiments with lentiviral vector coding for a green fluorescent protein (GFP) gene confirmed that the addition of CsH enhanced transgene expression levels and vector copy number per cell (VCN), while CD34⁺ cells remained viable and functional. Notably, the production of colony-forming cells (CFC) remained unaffected unless very high VCN values were reached. In a second step, CD34⁺ cells obtained from the CB of newborns with homozygous (<i>n</i> = 2) or heterozygous (<i>n</i> = 1) SCD mutations were transduced with the GLOBE-AS3 lentiviral vector coding for the HbAS3 anti-sickling beta globin. As with GFP, GLOBE-AS3 lentiviral transduction was clearly enhanced by CsH, leading to VCN > 2 and therapeutic levels of expression of the HbAS3. Moreover, the process did not affect the viability or functions of CFC. The combination of CB progenitors, the GLOBE-AS3 vector, and CsH is thus shown here to be a promising approach for the treatment of SCD.</p>","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":"896-903"},"PeriodicalIF":3.9,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142590553","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}