{"topic":"gene-cell-therapy","sort":"top","limit":25,"offset":0,"count":25,"papers":[{"id":"doi:10.1038/s41573-019-0012-9","kind":"review","title":"Adeno-associated virus vector as a platform for gene therapy delivery","authors":["Dan Wang","Phillip W.L. Tai","Guangping Gao"],"author_count":3,"year":2019,"published":"2019-02-01","venue":"Nature Reviews Drug Discovery","cited_by":2442,"doi":"10.1038/s41573-019-0012-9","arxiv_id":null,"nct_id":null,"source_url":"https://doi.org/10.1038/s41573-019-0012-9","archive_url":"https://space-kitty.com/papers/doi:10.1038/s41573-019-0012-9","updated":null,"pmid":"30710128","pmcid":null,"openalex_id":"W2913212173","pdf_url":null,"abstract":null,"abstract_license":null,"license":null,"is_open_access":true,"retracted":false,"peer_reviewed":null,"categories":["Virus-based gene therapy research"],"details":null,"provenance":"openalex","attribution":"Metadata and citation counts: OpenAlex (CC0)."},{"id":"doi:10.1056/nejmoa1108046","kind":"article","title":"Adenovirus-Associated Virus Vector–Mediated Gene Transfer in Hemophilia B","authors":["Amit Chunilal Nathwani","Edward G. D. Tuddenham","Savita Rangarajan","Cecilia Rosales","Jenny McIntosh","David C. Linch","Pratima Chowdary","Anne F. Riddell","Arnulfo Pie","Chris Harrington","James P. O’Beirne","Keith Smith","John Pasi","Bertil E. Glader","Pradip K. Rustagi","Catherine Y. Ng","Mark A. Kay","Junfang Zhou","Yunyu Spence","Christopher L. Morton","James A. Allay","John Coleman","Susan Sleep","John M. Cunningham","Deo Kumar Srivastava"],"author_count":32,"year":2011,"published":"2011-12-10","venue":"New England Journal of Medicine","cited_by":1863,"doi":"10.1056/nejmoa1108046","arxiv_id":null,"nct_id":null,"source_url":"https://doi.org/10.1056/nejmoa1108046","archive_url":"https://space-kitty.com/papers/doi:10.1056/nejmoa1108046","updated":null,"pmid":"22149959","pmcid":null,"openalex_id":"W2122304523","pdf_url":"https://www.nejm.org/doi/pdf/10.1056/NEJMoa1108046?articleTools=true","abstract":null,"abstract_license":null,"license":null,"is_open_access":true,"retracted":false,"peer_reviewed":null,"categories":["Hemophilia Treatment and Research"],"details":null,"provenance":"openalex","attribution":"Metadata and citation counts: OpenAlex (CC0)."},{"id":"doi:10.1038/s41392-024-01780-w","kind":"review","title":"Adeno-associated virus as a delivery vector for gene therapy of human diseases","authors":["Jiang-Hui Wang","Dominic J. Gessler","Wei Zhan","T. F. Gallagher","Guangping Gao"],"author_count":5,"year":2024,"published":"2024-04-02","venue":"Signal Transduction and Targeted Therapy","cited_by":852,"doi":"10.1038/s41392-024-01780-w","arxiv_id":null,"nct_id":null,"source_url":"https://doi.org/10.1038/s41392-024-01780-w","archive_url":"https://space-kitty.com/papers/doi:10.1038/s41392-024-01780-w","updated":null,"pmid":"38565561","pmcid":null,"openalex_id":"W4393581315","pdf_url":"https://www.nature.com/articles/s41392-024-01780-w.pdf","abstract":"Adeno-associated virus (AAV) has emerged as a pivotal delivery tool in clinical gene therapy owing to its minimal pathogenicity and ability to establish long-term gene expression in different tissues. Recombinant AAV (rAAV) has been engineered for enhanced specificity and developed as a tool for treating various diseases. However, as rAAV is being more widely used as a therapy, the increased demand has created challenges for the existing manufacturing methods. Seven rAAV-based gene therapy products have received regulatory approval, but there continue to be concerns about safely using high-dose viral therapies in humans, including immune responses and adverse effects such as genotoxicity, hepatotoxicity, thrombotic microangiopathy, and neurotoxicity. In this review, we explore AAV biology with an emphasis on current vector engineering strategies and manufacturing technologies. We discuss how rAAVs are being employed in ongoing clinical trials for ocular, neurological, metabolic, hematological, neuromuscular, and cardiovascular diseases as well as cancers. We outline immune responses triggered by rAAV, address associated side effects, and discuss strategies to mitigate these reactions. We hope that discussing recent advancements and current challenges in the field will be a helpful guide for researchers and clinicians navigating the ever-evolving landscape of rAAV-based gene therapy.","abstract_license":"CC-BY (publisher license, via OpenAlex)","license":"cc-by","is_open_access":true,"retracted":false,"peer_reviewed":null,"categories":["Virus-based gene therapy research"],"details":null,"provenance":"openalex","attribution":"Abstract of \"Adeno-associated virus as a delivery vector for gene therapy of human diseases\" by Jiang-Hui Wang, Dominic J. Gessler, Wei Zhan et al., https://doi.org/10.1038/s41392-024-01780-w, used under its Creative Commons Attribution license (CC-BY); markup removed, otherwise unmodified."},{"id":"doi:10.1007/s40259-017-0234-5","kind":"review","title":"Adeno-Associated Virus (AAV) as a Vector for Gene Therapy","authors":["Michael F. Naso","Brian E. Tomkowicz","William L. Perry","William R. Strohl"],"author_count":4,"year":2017,"published":"2017-07-01","venue":"BioDrugs","cited_by":1359,"doi":"10.1007/s40259-017-0234-5","arxiv_id":null,"nct_id":null,"source_url":"https://doi.org/10.1007/s40259-017-0234-5","archive_url":"https://space-kitty.com/papers/doi:10.1007/s40259-017-0234-5","updated":null,"pmid":"28669112","pmcid":null,"openalex_id":"W2727482182","pdf_url":"https://link.springer.com/content/pdf/10.1007/s40259-017-0234-5.pdf","abstract":null,"abstract_license":null,"license":"cc-by-nc","is_open_access":true,"retracted":false,"peer_reviewed":null,"categories":["Virus-based gene therapy research"],"details":null,"provenance":"openalex","attribution":"Metadata and citation counts: OpenAlex (CC0)."},{"id":"doi:10.1038/s41576-019-0205-4","kind":"review","title":"Engineering adeno-associated virus vectors for gene therapy","authors":["Chengwen Li","Richard Jude Samulski"],"author_count":2,"year":2020,"published":"2020-02-10","venue":"Nature Reviews Genetics","cited_by":1175,"doi":"10.1038/s41576-019-0205-4","arxiv_id":null,"nct_id":null,"source_url":"https://doi.org/10.1038/s41576-019-0205-4","archive_url":"https://space-kitty.com/papers/doi:10.1038/s41576-019-0205-4","updated":null,"pmid":"32042148","pmcid":null,"openalex_id":"W3004887743","pdf_url":null,"abstract":null,"abstract_license":null,"license":null,"is_open_access":false,"retracted":false,"peer_reviewed":null,"categories":["Virus-based gene therapy research"],"details":null,"provenance":"openalex","attribution":"Metadata and citation counts: OpenAlex (CC0)."},{"id":"doi:10.1080/10717544.2018.1474964","kind":"review","title":"Delivering CRISPR: a review of the challenges and approaches","authors":["Christopher A. Lino","Jason C. Harper","James P. Carney","Jerilyn A. Timlin"],"author_count":4,"year":2018,"published":"2018-01-01","venue":"Drug Delivery","cited_by":1184,"doi":"10.1080/10717544.2018.1474964","arxiv_id":null,"nct_id":null,"source_url":"https://doi.org/10.1080/10717544.2018.1474964","archive_url":"https://space-kitty.com/papers/doi:10.1080/10717544.2018.1474964","updated":null,"pmid":"29801422","pmcid":null,"openalex_id":"W2804566227","pdf_url":null,"abstract":"Gene therapy has long held promise to correct a variety of human diseases and defects. Discovery of the Clustered Regularly-Interspaced Short Palindromic Repeats (CRISPR), the mechanism of the CRISPR-based prokaryotic adaptive immune system (CRISPR-associated system, Cas), and its repurposing into a potent gene editing tool has revolutionized the field of molecular biology and generated excitement for new and improved gene therapies. Additionally, the simplicity and flexibility of the CRISPR/Cas9 site-specific nuclease system has led to its widespread use in many biological research areas including development of model cell lines, discovering mechanisms of disease, identifying disease targets, development of transgene animals and plants, and transcriptional modulation. In this review, we present the brief history and basic mechanisms of the CRISPR/Cas9 system and its predecessors (ZFNs and TALENs), lessons learned from past human gene therapy efforts, and recent modifications of CRISPR/Cas9 to provide functions beyond gene editing. We introduce several factors that influence CRISPR/Cas9 efficacy which must be addressed before effective in vivo human gene therapy can be realized. The focus then turns to the most difficult barrier to potential in vivo use of CRISPR/Cas9, delivery. We detail the various cargos and delivery vehicles reported for CRISPR/Cas9, including physical delivery methods (e.g. microinjection; electroporation), viral delivery methods (e.g. adeno-associated virus (AAV); full-sized adenovirus and lentivirus), and non-viral delivery methods (e.g. liposomes; polyplexes; gold particles), and discuss their relative merits. We also examine several technologies that, while not currently reported for CRISPR/Cas9 delivery, appear to have promise in this field. The therapeutic potential of CRISPR/Cas9 is vast and will only increase as the technology and its delivery improves.","abstract_license":"CC-BY (publisher license, via OpenAlex)","license":"cc-by","is_open_access":true,"retracted":false,"peer_reviewed":null,"categories":["CRISPR and Genetic Engineering"],"details":null,"provenance":"openalex","attribution":"Abstract of \"Delivering CRISPR: a review of the challenges and approaches\" by Christopher A. Lino, Jason C. Harper, James P. Carney et al., https://doi.org/10.1080/10717544.2018.1474964, used under its Creative Commons Attribution license (CC-BY); markup removed, otherwise unmodified."},{"id":"doi:10.1089/hum.2009.182","kind":"article","title":"Prevalence of Serum IgG and Neutralizing Factors Against Adeno-Associated Virus (AAV) Types 1, 2, 5, 6, 8, and 9 in the Healthy Population: Implications for Gene Therapy Using AAV Vectors","authors":["Sylvie Boutin","Virginie Monteilhet","Philippe Veron","Christian Leborgne","Olivier Benvéniste","M. Montus","Carole Masurier"],"author_count":7,"year":2010,"published":"2010-01-22","venue":"Human Gene Therapy","cited_by":970,"doi":"10.1089/hum.2009.182","arxiv_id":null,"nct_id":null,"source_url":"https://doi.org/10.1089/hum.2009.182","archive_url":"https://space-kitty.com/papers/doi:10.1089/hum.2009.182","updated":null,"pmid":"20095819","pmcid":null,"openalex_id":"W2082025265","pdf_url":null,"abstract":null,"abstract_license":null,"license":null,"is_open_access":false,"retracted":false,"peer_reviewed":null,"categories":["Virus-based gene therapy research"],"details":null,"provenance":"openalex","attribution":"Metadata and citation counts: OpenAlex (CC0)."},{"id":"doi:10.3389/fimmu.2022.975803","kind":"review","title":"Immunogenicity and toxicity of AAV gene therapy","authors":["Hildegund C.J. Ertl"],"author_count":1,"year":2022,"published":"2022-08-12","venue":"Frontiers in Immunology","cited_by":397,"doi":"10.3389/fimmu.2022.975803","arxiv_id":null,"nct_id":null,"source_url":"https://doi.org/10.3389/fimmu.2022.975803","archive_url":"https://space-kitty.com/papers/doi:10.3389/fimmu.2022.975803","updated":null,"pmid":"36032092","pmcid":"PMC9411526","openalex_id":"W4291164838","pdf_url":"https://www.frontiersin.org/articles/10.3389/fimmu.2022.975803/pdf","abstract":"Gene transfer using adeno-associated viral (AAV) vectors has made tremendous progress in the last decade and has achieved cures of debilitating diseases such as hemophilia A and B. Nevertheless, progress is still being hampered by immune responses against the AAV capsid antigens or the transgene products. Immunosuppression designed to blunt T cell responses has shown success in some patients but failed in others especially if they received very high AAV vectors doses. Although it was initially thought that AAV vectors induce only marginal innate responses below the threshold of systemic symptoms recent trials have shown that complement activation can results in serious adverse events. Dorsal root ganglia toxicity has also been identified as a complication of high vector doses as has severe hepatotoxicity. Most of the critical complications occur in patients who are treated with very high vector doses indicating that the use of more efficient AAV vectors to allow for dose sparing or giving smaller doses repeatedly, the latter in conjunction with antibody or B cell depleting measures, should be explored.","abstract_license":"CC-BY (publisher license, via OpenAlex)","license":"cc-by","is_open_access":true,"retracted":false,"peer_reviewed":null,"categories":["Virus-based gene therapy research"],"details":null,"provenance":"openalex+europepmc","attribution":"Abstract of \"Immunogenicity and toxicity of AAV gene therapy\" by Hildegund C.J. Ertl, https://doi.org/10.3389/fimmu.2022.975803, used under its Creative Commons Attribution license (CC-BY); markup removed, otherwise unmodified."},{"id":"doi:10.1182/blood-2013-01-306647","kind":"review","title":"Immune responses to AAV vectors: overcoming barriers to successful gene therapy","authors":["Federico Mingozzi","Katherine A. High"],"author_count":2,"year":2013,"published":"2013-04-17","venue":"Blood","cited_by":955,"doi":"10.1182/blood-2013-01-306647","arxiv_id":null,"nct_id":null,"source_url":"https://doi.org/10.1182/blood-2013-01-306647","archive_url":"https://space-kitty.com/papers/doi:10.1182/blood-2013-01-306647","updated":null,"pmid":"23596044","pmcid":null,"openalex_id":"W1994064996","pdf_url":null,"abstract":null,"abstract_license":null,"license":null,"is_open_access":true,"retracted":false,"peer_reviewed":null,"categories":["Virus-based gene therapy research"],"details":null,"provenance":"openalex","attribution":"Metadata and citation counts: OpenAlex (CC0)."},{"id":"doi:10.1038/s41587-022-01219-z","kind":"article","title":"Functional, metabolic and transcriptional maturation of human pancreatic islets derived from stem cells","authors":["Balboa D","Barsby T","Lithovius V","Saarimäki-Vire J","Omar-Hmeadi M","Dyachok O","Montaser H","Lund PE","Yang M","Ibrahim H","Näätänen A","Chandra V","Vihinen H","Jokitalo E","Kvist J","Ustinov J","Nieminen AI","Kuuluvainen E","Hietakangas V","Katajisto P","Lau J","Carlsson PO","Barg S","Tengholm A","Otonkoski T"],"author_count":25,"year":2022,"published":"2022-03-03","venue":"Nature biotechnology","cited_by":359,"doi":"10.1038/s41587-022-01219-z","arxiv_id":null,"nct_id":null,"source_url":"https://doi.org/10.1038/s41587-022-01219-z","archive_url":"https://space-kitty.com/papers/doi:10.1038/s41587-022-01219-z","updated":null,"pmid":"35241836","pmcid":"PMC9287162","openalex_id":null,"pdf_url":"https://europepmc.org/articles/PMC9287162/pdf","abstract":"Transplantation of pancreatic islet cells derived from human pluripotent stem cells is a promising treatment for diabetes. Despite progress in the generation of stem-cell-derived islets (SC-islets), no detailed characterization of their functional properties has been conducted. Here, we generated functionally mature SC-islets using an optimized protocol and benchmarked them comprehensively against primary adult islets. Biphasic glucose-stimulated insulin secretion developed during in vitro maturation, associated with cytoarchitectural reorganization and the increasing presence of alpha cells. Electrophysiology, signaling and exocytosis of SC-islets were similar to those of adult islets. Glucose-responsive insulin secretion was achieved despite differences in glycolytic and mitochondrial glucose metabolism. Single-cell transcriptomics of SC-islets in vitro and throughout 6 months of engraftment in mice revealed a continuous maturation trajectory culminating in a transcriptional landscape closely resembling that of primary islets. Our thorough evaluation of SC-islet maturation highlights their advanced degree of functionality and supports their use in further efforts to understand and combat diabetes.","abstract_license":"CC-BY (article license as recorded by Europe PMC; abstract reproduced unmodified apart from markup removal)","license":"CC-BY","is_open_access":true,"retracted":false,"peer_reviewed":null,"categories":[],"details":null,"provenance":"europepmc","attribution":"Abstract of \"Functional, metabolic and transcriptional maturation of human pancreatic islets derived from stem cells\" by Balboa D, Barsby T, Lithovius V et al., https://doi.org/10.1038/s41587-022-01219-z, used under its Creative Commons Attribution license (CC-BY); markup removed, otherwise unmodified."},{"id":"doi:10.1016/j.omtm.2017.11.007","kind":"review","title":"Emerging Issues in AAV-Mediated In Vivo Gene Therapy","authors":["Pasqualina Colella","Giuseppe Ronzitti","Federico Mingozzi"],"author_count":3,"year":2017,"published":"2017-12-01","venue":"Molecular Therapy — Methods & Clinical Development","cited_by":879,"doi":"10.1016/j.omtm.2017.11.007","arxiv_id":null,"nct_id":null,"source_url":"https://doi.org/10.1016/j.omtm.2017.11.007","archive_url":"https://space-kitty.com/papers/doi:10.1016/j.omtm.2017.11.007","updated":null,"pmid":"29326962","pmcid":null,"openalex_id":"W2774511679","pdf_url":"http://www.cell.com/article/S2329050117301237/pdf","abstract":null,"abstract_license":null,"license":"cc-by-nc-nd","is_open_access":true,"retracted":false,"peer_reviewed":null,"categories":["Virus-based gene therapy research"],"details":null,"provenance":"openalex","attribution":"Metadata and citation counts: OpenAlex (CC0)."},{"id":"doi:10.1038/nrg2988","kind":"review","title":"Therapeutic in vivo gene transfer for genetic disease using AAV: progress and challenges","authors":["Federico Mingozzi","Katherine A. High"],"author_count":2,"year":2011,"published":"2011-04-18","venue":"Nature Reviews Genetics","cited_by":893,"doi":"10.1038/nrg2988","arxiv_id":null,"nct_id":null,"source_url":"https://doi.org/10.1038/nrg2988","archive_url":"https://space-kitty.com/papers/doi:10.1038/nrg2988","updated":null,"pmid":"21499295","pmcid":null,"openalex_id":"W2012894204","pdf_url":null,"abstract":null,"abstract_license":null,"license":null,"is_open_access":false,"retracted":false,"peer_reviewed":null,"categories":["Virus-based gene therapy research"],"details":null,"provenance":"openalex","attribution":"Metadata and citation counts: OpenAlex (CC0)."},{"id":"doi:10.1016/j.ymthe.2020.12.007","kind":"review","title":"Current Clinical Applications of In Vivo Gene Therapy with AAVs","authors":["Jerry R. Mendell","Samiah A. Al-Zaidy","Louise R. Rodino‐Klapac","Kimberly Goodspeed","Steven James Gray","Christine Nichols Kay","Sanford L. Boye","Lindsey A. George","Stephanie M. Salabarria","Manuela Corti","Barry J. Byrne","Jacques P. Tremblay"],"author_count":13,"year":2020,"published":"2020-12-10","venue":"Molecular Therapy","cited_by":743,"doi":"10.1016/j.ymthe.2020.12.007","arxiv_id":null,"nct_id":null,"source_url":"https://doi.org/10.1016/j.ymthe.2020.12.007","archive_url":"https://space-kitty.com/papers/doi:10.1016/j.ymthe.2020.12.007","updated":null,"pmid":"33309881","pmcid":null,"openalex_id":"W3111331330","pdf_url":"http://www.cell.com/article/S152500162030664X/pdf","abstract":"Hereditary diseases are caused by mutations in genes, and more than 7,000 rare diseases affect over 30 million Americans. For more than 30 years, hundreds of researchers have maintained that genetic modifications would provide effective treatments for many inherited human diseases, offering durable and possibly curative clinical benefit with a single treatment. This review is limited to gene therapy using adeno-associated virus (AAV) because the gene delivered by this vector does not integrate into the patient genome and has a low immunogenicity. There are now five treatments approved for commercialization and currently available, i.e., Luxturna, Zolgensma, the two chimeric antigen receptor T cell (CAR-T) therapies (Yescarta and Kymriah), and Strimvelis (the gammaretrovirus approved for adenosine deaminase-severe combined immunodeficiency [ADA-SCID] in Europe). Dozens of other treatments are under clinical trials. The review article presents a broad overview of the field of therapy by in vivo gene transfer. We review gene therapy for neuromuscular disorders (spinal muscular atrophy [SMA]; Duchenne muscular dystrophy [DMD]; X-linked myotubular myopathy [XLMTM]; and diseases of the central nervous system, including Alzheimer's disease, Parkinson's disease, Canavan disease, aromatic l-amino acid decarboxylase [AADC] deficiency, and giant axonal neuropathy), ocular disorders (Leber congenital amaurosis, age-related macular degeneration [AMD], choroideremia, achromatopsia, retinitis pigmentosa, and X-linked retinoschisis), the bleeding disorder hemophilia, and lysosomal storage disorders.","abstract_license":"CC-BY (publisher license, via OpenAlex)","license":"cc-by","is_open_access":true,"retracted":false,"peer_reviewed":null,"categories":["Virus-based gene therapy research"],"details":null,"provenance":"openalex","attribution":"Abstract of \"Current Clinical Applications of In Vivo Gene Therapy with AAVs\" by Jerry R. Mendell, Samiah A. Al-Zaidy, Louise R. Rodino‐Klapac et al., https://doi.org/10.1016/j.ymthe.2020.12.007, used under its Creative Commons Attribution license (CC-BY); markup removed, otherwise unmodified."},{"id":"doi:10.1016/s0140-6736(13)62117-0","kind":"article","title":"Retinal gene therapy in patients with choroideremia: initial findings from a phase 1/2 clinical trial","authors":["Robert Edward MacLaren","Markus Groppe","Alun R. Barnard","Charles L. Cottriall","Tanya Tolmachova","Leonard William Seymour","Kelly Reed Clark","Matthew J. During","Frans P.M. Cremers","Graeme Charles M. Black","Andrew John Lotery","Susan M. Downes","Andrew R. Webster","Miguel C. Seabra"],"author_count":14,"year":2014,"published":"2014-01-15","venue":"The Lancet","cited_by":796,"doi":"10.1016/s0140-6736(13)62117-0","arxiv_id":null,"nct_id":null,"source_url":"https://doi.org/10.1016/s0140-6736(13)62117-0","archive_url":"https://space-kitty.com/papers/doi:10.1016/s0140-6736(13)62117-0","updated":null,"pmid":"24439297","pmcid":null,"openalex_id":"W2126115955","pdf_url":"http://www.thelancet.com/article/S0140673613621170/pdf","abstract":null,"abstract_license":null,"license":null,"is_open_access":true,"retracted":false,"peer_reviewed":null,"categories":["Retinal Development and Disorders"],"details":null,"provenance":"openalex","attribution":"Metadata and citation counts: OpenAlex (CC0)."},{"id":"doi:10.1038/nrg3742","kind":"review","title":"Engineering adeno-associated viruses for clinical gene therapy","authors":["Melissa A. Kotterman","David V. Schaffer"],"author_count":2,"year":2014,"published":"2014-05-20","venue":"Nature Reviews Genetics","cited_by":761,"doi":"10.1038/nrg3742","arxiv_id":null,"nct_id":null,"source_url":"https://doi.org/10.1038/nrg3742","archive_url":"https://space-kitty.com/papers/doi:10.1038/nrg3742","updated":null,"pmid":"24840552","pmcid":null,"openalex_id":"W2133171074","pdf_url":null,"abstract":null,"abstract_license":null,"license":null,"is_open_access":true,"retracted":false,"peer_reviewed":null,"categories":["Virus-based gene therapy research"],"details":null,"provenance":"openalex","attribution":"Metadata and citation counts: OpenAlex (CC0)."},{"id":"doi:10.1016/j.ymthe.2019.12.010","kind":"review","title":"AAV Vector Immunogenicity in Humans: A Long Journey to Successful Gene Transfer","authors":["Helena Costa Verdera","Klaudia Kuranda","Federico Mingozzi"],"author_count":3,"year":2020,"published":"2020-01-09","venue":"Molecular Therapy","cited_by":639,"doi":"10.1016/j.ymthe.2019.12.010","arxiv_id":null,"nct_id":null,"source_url":"https://doi.org/10.1016/j.ymthe.2019.12.010","archive_url":"https://space-kitty.com/papers/doi:10.1016/j.ymthe.2019.12.010","updated":null,"pmid":"31972133","pmcid":null,"openalex_id":"W3000219265","pdf_url":"http://www.cell.com/article/S1525001620300034/pdf","abstract":null,"abstract_license":null,"license":"cc-by-nc-nd","is_open_access":true,"retracted":false,"peer_reviewed":null,"categories":["Virus-based gene therapy research"],"details":null,"provenance":"openalex","attribution":"Metadata and citation counts: OpenAlex (CC0)."},{"id":"doi:10.1038/s41467-020-17165-w","kind":"article","title":"Pre-clinical study of induced pluripotent stem cell-derived dopaminergic progenitor cells for Parkinson's disease","authors":["Doi D","Magotani H","Kikuchi T","Ikeda M","Hiramatsu S","Yoshida K","Amano N","Nomura M","Umekage M","Morizane A","Takahashi J"],"author_count":11,"year":2020,"published":"2020-07-06","venue":"Nature communications","cited_by":287,"doi":"10.1038/s41467-020-17165-w","arxiv_id":null,"nct_id":null,"source_url":"https://doi.org/10.1038/s41467-020-17165-w","archive_url":"https://space-kitty.com/papers/doi:10.1038/s41467-020-17165-w","updated":null,"pmid":"32632153","pmcid":"PMC7338530","openalex_id":null,"pdf_url":"https://europepmc.org/articles/PMC7338530/pdf","abstract":"Induced pluripotent stem cell (iPSC)-derived dopaminergic (DA) neurons are an expected source for cell-based therapies for Parkinson's disease (PD). The regulatory criteria for the clinical application of these therapies, however, have not been established. Here we show the results of our pre-clinical study, in which we evaluate the safety and efficacy of dopaminergic progenitors (DAPs) derived from a clinical-grade human iPSC line. We confirm the characteristics of DAPs by in vitro analyses. We also verify that the DAP population include no residual undifferentiated iPSCs or early neural stem cells and have no genetic aberration in cancer-related genes. Furthermore, in vivo studies using immunodeficient mice reveal no tumorigenicity or toxicity of the cells. When the DAPs are transplanted into the striatum of 6-OHDA-lesioned rats, the animals show behavioral improvement. Based on these results, we started a clinical trial to treat PD patients in 2018.","abstract_license":"CC-BY (article license as recorded by Europe PMC; abstract reproduced unmodified apart from markup removal)","license":"CC-BY","is_open_access":true,"retracted":false,"peer_reviewed":null,"categories":[],"details":null,"provenance":"europepmc","attribution":"Abstract of \"Pre-clinical study of induced pluripotent stem cell-derived dopaminergic progenitor cells for Parkinson's disease\" by Doi D, Magotani H, Kikuchi T et al., https://doi.org/10.1038/s41467-020-17165-w, used under its Creative Commons Attribution license (CC-BY); markup removed, otherwise unmodified."},{"id":"doi:10.1126/scitranslmed.3005708","kind":"article","title":"In Vivo–Directed Evolution of a New Adeno-Associated Virus for Therapeutic Outer Retinal Gene Delivery from the Vitreous","authors":["Deniz Dalkara","Leah C. Byrne","Ryan R. Klimczak","Meike Visel","Lu Yin","William H. Merigan","John G. Flannery","David V. Schaffer"],"author_count":8,"year":2013,"published":"2013-06-12","venue":"Science Translational Medicine","cited_by":733,"doi":"10.1126/scitranslmed.3005708","arxiv_id":null,"nct_id":null,"source_url":"https://doi.org/10.1126/scitranslmed.3005708","archive_url":"https://space-kitty.com/papers/doi:10.1126/scitranslmed.3005708","updated":null,"pmid":"23761039","pmcid":null,"openalex_id":"W2160986529","pdf_url":null,"abstract":null,"abstract_license":null,"license":null,"is_open_access":false,"retracted":false,"peer_reviewed":null,"categories":["Virus-based gene therapy research"],"details":null,"provenance":"openalex","attribution":"Metadata and citation counts: OpenAlex (CC0)."},{"id":"doi:10.1089/hum.2020.167","kind":"article","title":"Adeno-Associated Virus-Induced Dorsal Root Ganglion Pathology","authors":["Juliette Hordeaux","Elizabeth L. Buza","Cecilia Dyer","Tamara L. Goode","Thomas Warner Mitchell","Laura K. Richman","Nathan Denton","Christian J. Hinderer","Nathan Katz","Ralf S. Schmid","R. Colin Miller","Gourav Roy Choudhury","Makoto Horiuchi","Kalyani Nambiar","Hanying Yan","Mingyao Li","James M. Wilson"],"author_count":17,"year":2020,"published":"2020-08-01","venue":"Human Gene Therapy","cited_by":256,"doi":"10.1089/hum.2020.167","arxiv_id":null,"nct_id":null,"source_url":"https://doi.org/10.1089/hum.2020.167","archive_url":"https://space-kitty.com/papers/doi:10.1089/hum.2020.167","updated":null,"pmid":"32845779","pmcid":null,"openalex_id":"W3081415673","pdf_url":null,"abstract":"The administration of adeno-associated virus (AAV) vectors to nonhuman primates (NHP) via the blood or cerebrospinal fluid (CSF) can lead to dorsal root ganglion (DRG) pathology. The pathology is minimal to moderate in most cases; clinically silent in affected animals; and characterized by mononuclear cell infiltrates, neuronal degeneration, and secondary axonopathy of central and peripheral axons on histopathological analysis. We aggregated data from 33 nonclinical studies in 256 NHP and performed a meta-analysis of the severity of DRG pathology to compare different routes of administration, dose, time course, study conduct, age of the animals, sex, capsid, promoter, capsid purification method, and transgene. DRG pathology was observed in 83% of NHP that were administered AAV through the CSF, and 32% of NHP that received an intravenous (IV) injection. We show that dose and age at injection significantly affected the severity whereas sex had no impact. DRG pathology was minimal at acute time points ( i.e ., <14 days), similar from one to 5 months post-injection, and was less severe after 6 months. Vector purification method had no impact, and all capsids and promoters that we tested resulted in some DRG pathology. The data presented here from five different capsids, five different promoters, and 20 different transgenes suggest that DRG pathology is almost universal after AAV gene therapy in nonclinical studies using NHP. None of the animals receiving a therapeutic transgene displayed any clinical signs. Incorporation of sensitive techniques such as nerve-conduction velocity testing can show alterations in a minority of animals that correlate with the severity of peripheral nerve axonopathy. Monitoring sensory neuropathies in human central nervous system and high-dose IV clinical studies seems prudent to determine the functional consequences of DRG pathology.","abstract_license":"CC-BY (publisher license, via OpenAlex)","license":"cc-by","is_open_access":true,"retracted":false,"peer_reviewed":null,"categories":["Virus-based gene therapy research"],"details":null,"provenance":"openalex+europepmc","attribution":"Abstract of \"Adeno-Associated Virus-Induced Dorsal Root Ganglion Pathology\" by Juliette Hordeaux, Elizabeth L. Buza, Cecilia Dyer et al., https://doi.org/10.1089/hum.2020.167, used under its Creative Commons Attribution license (CC-BY); markup removed, otherwise unmodified."},{"id":"doi:10.1038/s41422-023-00789-0","kind":"article","title":"Tuning charge density of chimeric antigen receptor optimizes tonic signaling and CAR-T cell fitness","authors":["Chen J","Qiu S","Li W","Wang K","Zhang Y","Yang H","Liu B","Li G","Li L","Chen M","Lan J","Niu J","He P","Cheng L","Fan G","Liu X","Song X","Xu C","Wu H","Wang H"],"author_count":20,"year":2023,"published":"2023-03-08","venue":"Cell research","cited_by":176,"doi":"10.1038/s41422-023-00789-0","arxiv_id":null,"nct_id":null,"source_url":"https://doi.org/10.1038/s41422-023-00789-0","archive_url":"https://space-kitty.com/papers/doi:10.1038/s41422-023-00789-0","updated":null,"pmid":"36882513","pmcid":"PMC10156745","openalex_id":null,"pdf_url":"https://europepmc.org/articles/PMC10156745/pdf","abstract":"Tonic signaling of chimeric antigen receptor (CAR), i.e., the spontaneous CAR activation in the absence of tumor antigen stimulation, is considered to be a pivotal event controlling CAR-T efficacy. However, the molecular mechanism underlying the spontaneous CAR signals remains elusive. Here, we unveil that positively charged patches (PCPs) on the surface of the CAR antigen-binding domain mediate CAR clustering and result in CAR tonic signaling. For CARs with high tonic signaling (e.g., GD2.CAR and CSPG4.CAR), reducing PCPs on CARs or boosting ionic strength in the culture medium during ex vivo CAR-T cell expansion minimizes spontaneous CAR activation and alleviates CAR-T cell exhaustion. In contrast, introducing PCPs into the CAR with weak tonic signaling, such as CD19.CAR, results in improved in vivo persistence and superior antitumor function. These results demonstrate that CAR tonic signaling is induced and maintained by PCP-mediated CAR clustering. Notably, the mutations we generated to alter the PCPs maintain the antigen-binding affinity and specificity of the CAR. Therefore, our findings suggest that the rational tuning of PCPs to optimize tonic signaling and in vivo fitness of CAR-T cells is a promising design strategy for the next-generation CAR.","abstract_license":"CC-BY (article license as recorded by Europe PMC; abstract reproduced unmodified apart from markup removal)","license":"CC-BY","is_open_access":true,"retracted":false,"peer_reviewed":null,"categories":[],"details":null,"provenance":"europepmc","attribution":"Abstract of \"Tuning charge density of chimeric antigen receptor optimizes tonic signaling and CAR-T cell fitness\" by Chen J, Qiu S, Li W et al., https://doi.org/10.1038/s41422-023-00789-0, used under its Creative Commons Attribution license (CC-BY); markup removed, otherwise unmodified."},{"id":"doi:10.1016/j.ymthe.2022.06.004","kind":"review","title":"Evaluating the state of the science for adeno-associated virus integration: An integrated perspective","authors":["Sabatino DE","Bushman FD","Chandler RJ","Crystal RG","Davidson BL","Dolmetsch R","Eggan KC","Gao G","Gil-Farina I","Kay MA","McCarty DM","Montini E","Ndu A","Yuan J"],"author_count":14,"year":2022,"published":"2022-06-10","venue":"Molecular therapy : the journal of the American Society of Gene Therapy","cited_by":197,"doi":"10.1016/j.ymthe.2022.06.004","arxiv_id":null,"nct_id":null,"source_url":"https://doi.org/10.1016/j.ymthe.2022.06.004","archive_url":"https://space-kitty.com/papers/doi:10.1016/j.ymthe.2022.06.004","updated":null,"pmid":"35690906","pmcid":"PMC9372310","openalex_id":null,"pdf_url":"https://europepmc.org/articles/PMC9372310/pdf","abstract":"On August 18, 2021, the American Society of Gene and Cell Therapy (ASGCT) hosted a virtual roundtable on adeno-associated virus (AAV) integration, featuring leading experts in preclinical and clinical AAV gene therapy, to further contextualize and understand this phenomenon. Recombinant AAV (rAAV) vectors are used to develop therapies for many conditions given their ability to transduce multiple cell types, resulting in long-term expression of transgenes. Although most rAAV DNA typically remains episomal, some rAAV DNA becomes integrated into genomic DNA at a low frequency, and rAAV insertional mutagenesis has been shown to lead to tumorigenesis in neonatal mice. Currently, the risk of rAAV-mediated oncogenesis in humans is theoretical because no confirmed genotoxic events have been reported to date. However, because insertional mutagenesis has been reported in a small number of murine studies, there is a need to characterize this genotoxicity to inform research, regulatory needs, and patient care. The purpose of this white paper is to review the evidence of rAAV-related host genome integration in animal models and possible risks of insertional mutagenesis in patients. In addition, technical considerations, regulatory guidance, and bioethics are discussed.","abstract_license":"CC-BY (article license as recorded by Europe PMC; abstract reproduced unmodified apart from markup removal)","license":"CC-BY","is_open_access":true,"retracted":false,"peer_reviewed":null,"categories":[],"details":null,"provenance":"europepmc","attribution":"Abstract of \"Evaluating the state of the science for adeno-associated virus integration: An integrated perspective\" by Sabatino DE, Bushman FD, Chandler RJ et al., https://doi.org/10.1016/j.ymthe.2022.06.004, used under its Creative Commons Attribution license (CC-BY); markup removed, otherwise unmodified."},{"id":"doi:10.1038/d41573-021-00017-7","kind":"article","title":"The clinical landscape for AAV gene therapies","authors":["Dmitry Kuzmin","Maria V. Shutova","Natalie R. Johnston","Owen P. Smith","Vasily V. Fedorin","Yury S. Kukushkin","Johannes C.M. van der Loo","Elaine C Johnstone"],"author_count":8,"year":2021,"published":"2021-01-25","venue":"Nature Reviews Drug Discovery","cited_by":503,"doi":"10.1038/d41573-021-00017-7","arxiv_id":null,"nct_id":null,"source_url":"https://doi.org/10.1038/d41573-021-00017-7","archive_url":"https://space-kitty.com/papers/doi:10.1038/d41573-021-00017-7","updated":null,"pmid":"33495615","pmcid":null,"openalex_id":"W3124760643","pdf_url":null,"abstract":null,"abstract_license":null,"license":null,"is_open_access":false,"retracted":false,"peer_reviewed":null,"categories":["Virus-based gene therapy research"],"details":null,"provenance":"openalex","attribution":"Metadata and citation counts: OpenAlex (CC0)."},{"id":"doi:10.1146/annurev-virology-031413-085355","kind":"review","title":"AAV-Mediated Gene Therapy for Research and Therapeutic Purposes","authors":["Richard Jude Samulski","Nicholas Muzyczka"],"author_count":2,"year":2014,"published":"2014-10-01","venue":"Annual Review of Virology","cited_by":585,"doi":"10.1146/annurev-virology-031413-085355","arxiv_id":null,"nct_id":null,"source_url":"https://doi.org/10.1146/annurev-virology-031413-085355","archive_url":"https://space-kitty.com/papers/doi:10.1146/annurev-virology-031413-085355","updated":null,"pmid":"26958729","pmcid":null,"openalex_id":"W2139166113","pdf_url":"https://www.annualreviews.org/doi/pdf/10.1146/annurev-virology-031413-085355","abstract":null,"abstract_license":null,"license":null,"is_open_access":true,"retracted":false,"peer_reviewed":null,"categories":["Virus-based gene therapy research"],"details":null,"provenance":"openalex","attribution":"Metadata and citation counts: OpenAlex (CC0)."},{"id":"doi:10.1038/nbt.3469","kind":"article","title":"A dual AAV system enables the Cas9-mediated correction of a metabolic liver disease in newborn mice","authors":["Yang Yang","Lili Wang","Peter L. Bell","Deirdre McMenamin","Zhenning He","John White","Hongwei Yu","Chenyu Xu","Hiroki Morizono","Kiran Musunuru","Mark L. Batshaw","James M. Wilson"],"author_count":12,"year":2016,"published":"2016-02-01","venue":"Nature Biotechnology","cited_by":556,"doi":"10.1038/nbt.3469","arxiv_id":null,"nct_id":null,"source_url":"https://doi.org/10.1038/nbt.3469","archive_url":"https://space-kitty.com/papers/doi:10.1038/nbt.3469","updated":null,"pmid":"26829317","pmcid":null,"openalex_id":"W2253584908","pdf_url":null,"abstract":null,"abstract_license":null,"license":null,"is_open_access":true,"retracted":false,"peer_reviewed":null,"categories":["Virus-based gene therapy research"],"details":null,"provenance":"openalex","attribution":"Metadata and citation counts: OpenAlex (CC0)."},{"id":"doi:10.3389/fimmu.2013.00341","kind":"review","title":"Humoral Immune Response to AAV","authors":["Roberto Calcedo","James M. Wilson"],"author_count":2,"year":2013,"published":"2013-01-01","venue":"Frontiers in Immunology","cited_by":243,"doi":"10.3389/fimmu.2013.00341","arxiv_id":null,"nct_id":null,"source_url":"https://doi.org/10.3389/fimmu.2013.00341","archive_url":"https://space-kitty.com/papers/doi:10.3389/fimmu.2013.00341","updated":null,"pmid":"24151496","pmcid":"PMC3799231","openalex_id":"W2058864263","pdf_url":"https://www.frontiersin.org/articles/10.3389/fimmu.2013.00341/pdf","abstract":"Adeno-associated virus (AAV) is a member of the family Parvoviridae that has been widely used as a vector for gene therapy because of its safety profile, its ability to transduce both dividing and non-dividing cells, and its low immunogenicity. AAV has been detected in many different tissues of several animal species but has not been associated with any disease. As a result of natural infections, antibodies to AAV can be found in many animals including humans. It has been shown that pre-existing AAV antibodies can modulate the safety and efficacy of AAV vector-mediated gene therapy by blocking vector transduction or by redirecting distribution of AAV vectors to tissues other than the target organ. This review will summarize antibody responses against natural AAV infections, as well as AAV gene therapy vectors and their impact in the clinical development of AAV vectors for gene therapy. We will also review and discuss the various methods used for AAV antibody detection and strategies to overcome neutralizing antibodies in AAV-mediated gene therapy.","abstract_license":"CC-BY (publisher license, via OpenAlex)","license":"cc-by","is_open_access":true,"retracted":false,"peer_reviewed":null,"categories":["Virus-based gene therapy research"],"details":null,"provenance":"openalex+europepmc","attribution":"Abstract of \"Humoral Immune Response to AAV\" by Roberto Calcedo, James M. Wilson, https://doi.org/10.3389/fimmu.2013.00341, used under its Creative Commons Attribution license (CC-BY); markup removed, otherwise unmodified."}],"next":"https://space-kitty.com/api/v1/topics/gene-cell-therapy/papers?sort=top&limit=25&offset=25"}