Human gene therapy最新文献

{"title":"Comprehensive Review of Osteogenesis Imperfecta: Current Treatments and Future Innovations.","authors":"Sachin Chaugule, Christodoulos Kypros Constantinou, Aijaz Ahmad John, Dimitra Micha, Marelise Eekhoff, Ellen Gravallese, Guangping Gao, Jae-Hyuck Shim","doi":"10.1089/hum.2024.191","DOIUrl":"10.1089/hum.2024.191","url":null,"abstract":"<p><p>Osteogenesis imperfecta (OI) is a rare genetic disorder characterized by bone fragility due to reduced bone quality, often accompanied by low bone mass, recurrent fractures, hearing loss, skeletal abnormalities, and short stature. Pathogenic variants in over 20 genes lead to clinical and genetic variability in OI, resulting in diverse symptoms and severity. Current management involves a multidisciplinary approach, including antiresorptive medications, physiotherapy, occupational therapy, and orthopedic surgery, which provide symptomatic relief but no cure. Advancements in gene therapy technologies and stem cell therapies offer promising prospects for long-lasting or permanent solutions. This review provides a comprehensive overview of OI's classification, pathogenesis, and current treatment options. It also explores emerging biotechnologies for stem cells and gene-targeted therapies in OI. The potential of these innovative therapies and their clinical implementation challenges are evaluated, focusing on their imminent success in treating bone disorders.</p>","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":"597-617"},"PeriodicalIF":3.9,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143398879","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 Therapy Development: Early Planning and Regulatory Considerations to Advance the Platform Vector Gene Therapy Program.","authors":"Richa Madan Lomash, Jean Dehdashti, Oleg A Shchelochkov, Randy J Chandler, Lina Li, Irini Manoli, Jennifer L Sloan, Pramod Terse, Xin Xu, Dimah Saade, Rodica Stan, Philip J Brooks, Donald C Lo, Carsten G Bönnemann, Charles P Venditti, Anne R Pariser, Elizabeth A Ottinger","doi":"10.1089/hum.2024.230","DOIUrl":"10.1089/hum.2024.230","url":null,"abstract":"<p><p>Gene therapy development presents multiple challenges, and early planning is vital in the successful implementation of such programs. The Platform Vector Gene Therapy (PaVe-GT) program is a National Institutes of Health (NIH) initiative developing adeno-associated virus (AAV) gene therapies for four low-prevalence rare diseases. Utilizing the platform-based approach, the program aims to incorporate efficiencies throughout the preclinical and clinical development processes followed by public dissemination of scientific and regulatory learnings. Early in development, the establishment of a Target Product Profile (TPP) by the research team is a critical step to guide product development and align preclinical studies to clinical objectives. Based on the specific needs of the investigational product as defined in the TPP, an overall regulatory strategy can then be outlined to meet the regulatory requirements for the first-in-human clinical trials. During the preclinical phase of development, sponsors may request meetings with the Food and Drug Administration (FDA) to gather feedback on the planned studies and regulatory strategy. To pave the way for PaVe-GT's first investigational AAV gene therapy lead candidate, AAV9-hPCCA, we sought early feedback from the FDA utilizing an INitial Targeted Engagement for Regulatory Advice on CBER/CDER ProducTs (INTERACT) meeting. Here, we elaborate on the value of establishing a TPP and the FDA INTERACT meeting by including our initial AAV9-hPCCA TPP, detailing our INTERACT meeting experience, providing all corresponding regulatory documentation, and highlighting lessons learned. The regulatory documents along with templates developed by our program can also be found on the PaVe-GT website (https://pave-gt.ncats.nih.gov/). This communication aims to provide stakeholders with resources that can be applied to drug development programs in establishing a viable regulatory path to clinical trial initiation.</p>","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":"653-662"},"PeriodicalIF":3.9,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143457791","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-Mediated Gene Transfer of WDR45 Corrects Neurological Deficits in the Mouse Model of Beta-Propeller Protein-Associated Neurodegeneration.","authors":"Maria Carla Carisi, Claire Shamber, Martha Bishop, Madison Sangster, Uma Chandrachud, Brandon Meyerink, Louis Jean Pilaz, Yulia Grishchuk","doi":"10.1089/hum.2024.224","DOIUrl":"10.1089/hum.2024.224","url":null,"abstract":"<p><p>Beta-propeller protein-associated neurodegeneration (BPAN) is an ultra-rare, X-linked dominant, neurodevelopmental, and neurodegenerative disease caused by loss-of-function mutations in the <i>WDR45</i> gene. It manifests in neurodevelopmental delay and seizures followed by secondary neurological decline with dystonia/parkinsonism and dementia in adolescence and early adulthood and is characterized by progressive accumulation of iron in the basal ganglia. <i>WDR45</i> encodes β-propeller-shaped scaffold protein, or WD repeat domain phosphoinositide-interacting protein 4 (WIPI4), which plays an important role in autophagosome formation. While the mechanisms of how WIPI4 loss of function results in neurological decline and brain pathology have not yet been established, findings of lower autophagic activity provide a direct link between impaired autophagy and neurological disease in BPAN. Here we performed phenotypical characterization of a novel mouse model of BPAN, Wdr45_ex9+1g>a mouse. We identified hyperactive behavior and reduction of autophagy markers in brain tissue in Wdr45_ex9+1g>a hemizygous males as early as at 2 months of age. Given the early onset and spectrum of neurological symptoms such as hyper-arousal and attention deficits in human patients, this model presents a disease-relevant phenotype and can be used in preclinical studies. We used this mouse model for a proof-of-concept study to evaluate whether adeno-associated virus (AAV)-mediated central nervous system (CNS)-targeted gene transfer of <i>WDR45</i> can provide therapeutic benefit and be considered a therapeutic paradigm for BPAN. We observed successful expression of human <i>WDR45</i> transcripts and WIPI4 protein in the brain tissue, rescue of hyperactive behavior, and correction of autophagy markers. These data demonstrate that <i>WDR45</i> gene transfer can be a promising therapeutic strategy for BPAN.</p>","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":"637-652"},"PeriodicalIF":3.9,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143467877","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":"Hum Gene Therapy Briefs March 2025.","authors":"Alex Philippidis","doi":"10.1089/hum.2025.017","DOIUrl":"https://doi.org/10.1089/hum.2025.017","url":null,"abstract":"","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":"36 5-6","pages":"593-596"},"PeriodicalIF":3.9,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143624453","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":"Minimally Humanized <i>Ezh2</i> Exon-18 Mouse Cell Lines Validate Preclinical CRISPR/Cas9 Approach to Treat Weaver Syndrome.","authors":"William T Gibson, Tess C Lengyell, Andrea J Korecki, Sanne M Janssen, Bethany A Adair, Daniel Gamu, Matthew C Lorincz, Elizabeth M Simpson","doi":"10.1089/hum.2024.170","DOIUrl":"10.1089/hum.2024.170","url":null,"abstract":"<p><p>Weaver syndrome is a rare neurodevelopmental disorder that encompasses macrocephaly, tall stature, obesity, brain anomalies, intellectual disability, and increased susceptibility to cancer. This dominant monogenic disorder is caused by germline variants in enhancer of zeste 2 polycomb repressive complex 2 subunit (<i>EZH2</i>), a key epigenetic writer. Unfortunately, there are no effective treatments for Weaver syndrome. However, preclinical results support the potential for therapeutic gains, despite the prenatal onset. Thus, for the first time, we tested whether CRISPR/Cas9 gene-editing strategies may be able to \"correct\" a Weaver syndrome variant at the DNA level. We initiated these preclinical studies by humanizing the region surrounding the most-common recurring patient-variant location in mouse embryonic stem cells (ESCs). Humanization ensures that DNA-binding strategies will be directly translatable to human cells and patients. We then introduced into ESCs the humanized region, but now carrying the Weaver syndrome <i>EZH2</i> variant c.2035C>T p.Arg684Cys, and characterized the enzymatic properties of this missense variant. Our data showed a significant and dramatic reduction in EZH2-enzymatic activity, supporting previous cell-free studies of this variant as well as <i>in vitro</i> and <i>in vivo</i> mouse work by other teams. Intriguingly, this most-common variant does not create a complete loss-of-function, but rather is a hypomorphic allele. Together with prior reports describing hypomorphic effects of missense <i>EZH2</i> variants, these results demonstrate that the etiology of Weaver syndrome does not require complete loss of EZH2 enzymatic activity. Toward therapy, we tested four CRISPR gene-editing strategies. We demonstrated that <i>Streptococcus pyogenes</i> Cas9 (<i>Sp</i>Cas9) showed the highest variant correction (70.5%), but unfortunately also the highest alteration of the nonvariant allele (21.1-26.2%), an important consideration for gene-editing treatment of a dominant syndrome. However, <i>Staphylococcus aureus</i> Cas9 (<i>Sa</i>Cas9) gave a variant correction (52.5%) that was not significantly different than <i>Sp</i>Cas9, and encouragingly the lowest alteration of the nonvariant allele (2.0%). Thus, the therapeutic strategy using the small <i>Sa</i>Cas9 enzyme, a size that allows flexibility in therapeutic delivery, was the most optimal for targeting the Weaver syndrome <i>EZH2</i> variant c.2035C>T p.Arg684Cys.</p>","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":"618-627"},"PeriodicalIF":3.9,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143448947","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":"Analysis of HIV-1-Based Lentiviral Vector Particle Composition by PacBio Long-Read Nucleic Acid Sequencing.","authors":"Saqlain Suleman, Mohammad S Khalifa, Serena Fawaz, Sharmin Alhaque, Yaghoub Chinea, Michael Themis","doi":"10.1089/hum.2024.121","DOIUrl":"10.1089/hum.2024.121","url":null,"abstract":"<p><p>Lentivirus (LV) vectors offer permanent delivery of therapeutic genes to the host through an RNA intermediate genome. They are one of the most commonly used vectors for clinical gene therapy of inherited disorders such as immune deficiencies and cancer immunotherapy. One of the most difficult challenges facing their widespread application to patients is the large-scale production of highly pure vector stocks. To improve vector production and downstream purification, there has been a recent investment in the United Kingdom to establish good manufacturing process (GMP)-licensed centers for manufacture and quality control. Other requirements for these vectors include their target cell specificity and tropism, how to regulate gene expression of the therapeutic payload and their potential side effects. Comprehensive detail on the full nucleic acid content of LV is unknown, even though they have entered clinical trials. With potential adverse effects in mind, it is important to identify these contents to assess their safety and purity. In this study, we used highly sensitive PacBio long-distance, next-generation sequencing of reverse-transcribed vector component RNA to investigate the nucleic acid composition of recombinant HIV-1 particles generated by human 293T packaging cells. In this article, we describe our findings of nucleic acids other than the recombinant vector genome that exist, which could potentially be delivered during gene transfer, and suggest that removal of these unwanted components be considered before clinical LV application.</p>","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":"628-636"},"PeriodicalIF":3.9,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143457795","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":"Prevalence of Neutralizing Antibodies to AAV2 and AAV9 in Individuals with Niemann-Pick Disease, Type C1.","authors":"Avani V Mylvara, Cristin D Davidson, Derek Alexander, Charles P Venditti, Forbes D Porter","doi":"10.1089/hum.2024.233","DOIUrl":"https://doi.org/10.1089/hum.2024.233","url":null,"abstract":"<p><p>Niemann-Pick disease, type C1 (NPC1), is a rare, fatal neurodegenerative disorder caused by pathological variations in <i>NPC1</i>. We and others have previously demonstrated the efficacy of systemic adeno-associated virus (AAV) gene therapy with AAV9 in murine models of NPC1. The presence of neutralizing antibodies (NAbs) caused by natural exposure to wildtype AAVs may impair AAV transduction efficacy and reduce or negate the benefit of gene therapy. In addition, there remains the question of whether individuals seroconvert with age and whether seroconversion limits the window of therapeutic efficacy. Thus, we assessed the prevalence of anti-AAV9 and anti-AAV2 NAbs in serum samples from 22 individuals with NPC1 at two different time points: one closer to diagnosis (0.9-17 years old) and another collected between 4 and 15 years later during follow-up (6-28 years old). At a titer of <1:5, we found that more than half of the cohort lacked NAbs against either AAV2 (68.2%) or AAV9 (59.1% at time 1, 63.6% at time 2). Notably, only 3 out of 22 individuals showed a transition from undetectable to detectable NAb titers, and most participants maintained stable titers over time, unaffected by age. These data support the feasibility of systemic or direct CNS AAV9 gene therapy in this patient population.</p>","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143523317","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":"Central Nervous System-Targeted Gene Therapy for the Treatment of Neurocognitive Deficits in Mucopolysaccharidosis Type II Mice.","authors":"Guoqing Chen, Xia Zhan, Xiaolan Gao, Mengni Yi, Huan Liang, Yixiong Chen, Qing Lin, Jun Yang, Shule Hou, Gustavo Maegawa, Huiwen Zhang","doi":"10.1089/hum.2024.229","DOIUrl":"https://doi.org/10.1089/hum.2024.229","url":null,"abstract":"<p><p>Mucopolysaccharidosis type II (MPS II) is an X-linked lysosomal storage disorder caused by pathogenic variants in the <i>IDS</i> gene encoding iduronate-2-sulfatase (IDS), which hydrolyzes sulfate groups in dermatan sulfate and heparan sulfate. The current treatment for MPS II includes enzyme replacement therapy and hematopoietic stem cell transplantation (HSCT). Both therapies have shown limited penetration through the blood-brain barrier. Anecdotal cases have been reported with the HSCT benefit to treat neurological problems in MPS II. Herein, we generated an MPS II mouse model using CRISPR/Cas9 to examine the effectiveness of CNS-directed, adeno-associated virus (AAV)2/9-mediated human IDS gene transfer in expressing sustained IDS and improving behavior performance in this model. The intracerebroventricular administration of AAV2/9-hIDS showed higher IDS activity in the central nervous system and better auditory function compared with those by intravenous administration. The results provide a strong proof of concept for the clinical translation of our approach to treating patients with MPS II and cognitive impairment.</p>","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143515379","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":"Hum Gene Therapy Briefs March 2025.","authors":"Alex Philippidis","doi":"10.1089/hum.2025.017","DOIUrl":"https://doi.org/10.1089/hum.2025.017","url":null,"abstract":"","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143483070","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":"A Comprehensive Review of Clinically Applied Adeno-Associated Virus-Based Gene Therapies for Ocular Disease.","authors":"Valerie G Hinsch, Sanford L Boye, Shannon E Boye","doi":"10.1089/hum.2024.252","DOIUrl":"https://doi.org/10.1089/hum.2024.252","url":null,"abstract":"<p><p>The eye is an ideal target for gene therapy due its accessibility, immune privilege, small size, and compartmentalization. Adeno-associated virus (AAV) is the gold standard vector for gene delivery and can be injected via multiple routes of administration to target different parts of this organ. The approval of Luxturna™, a subretinally delivered gene therapy for <i>RPE65</i>-associated Leber's congenital amaurosis, and the large number of successful proof of concept studies performed in animal models injected great momentum into the pursuit of additional AAV-based gene therapies for the treatment of retinal disease. This review provides a comprehensive summary of all subretinally, intravitreally, and suprachoroidally delivered AAV-based ocular gene therapies that have progressed to clinical stage. Attention is given to primary (safety) and secondary (efficacy) outcomes, or lack thereof. Lessons learned and future directions are addressed, both of which point to optimism that the ocular gene therapy field is poised for continued momentum and additional regulatory approvals.</p>","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143483028","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}