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Preclinical Systemic Delivery of Adeno-Associated α-Sarcoglycan Gene Transfer for Limb-Girdle Muscular Dystrophy Hum. Gene Ther. (IF 4.273) Pub Date : 2021-02-18 Danielle A. Griffin; Eric R. Pozsgai; Kristin N. Heller; Rachael A. Potter; Ellyn L. Peterson; Louise R. Rodino-Klapac
Limb-girdle muscular dystrophy type 2D/R3 (LGMD2D/R3) is a progressive muscular dystrophy that manifests with muscle weakness, respiratory abnormalities, and in rare cases cardiomyopathy. LGMD2D/R3 is caused by mutations in the SGCA gene resulting in loss of protein and concomitant loss of some or all components of the dystrophin-associated glycoprotein complex. The sgca-null (sgca−/−) mouse recapitulates
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Dose-Escalation Study of Systemically Delivered rAAVrh74.MHCK7.micro-dystrophin in the mdx Mouse Model of Duchenne Muscular Dystrophy Hum. Gene Ther. (IF 4.273) Pub Date : 2021-02-18 Rachael A. Potter; Danielle A. Griffin; Kristin N. Heller; Ellyn L. Peterson; Emma K. Clark; Jerry R. Mendell; Louise R. Rodino-Klapac
Duchenne muscular dystrophy (DMD) is a rare, X-linked, fatal, degenerative neuromuscular disease caused by mutations in the DMD gene. More than 2,000 mutations of the DMD gene are responsible for progressive loss of muscle strength, loss of ambulation, and generally respiratory and cardiac failure by age 30. Recently, gene transfer therapy has received widespread interest as a disease-modifying treatment
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The Identification and Development of a Novel Oncolytic Virus: Alphavirus M1 Hum. Gene Ther. (IF 4.273) Pub Date : 2021-02-16 Jing Cai; Guangmei Yan
Oncolytic virotherapy represents an ideal therapeutic platform for cancer in which natural or engineered viruses selectively replicate in and destroy tumor cells, whereas sparing normal cells. Oncolytic virotherapy is considered as a key contributor in modern immunotherapy. However, several challenges remain with regard to exploiting the potential of oncolytic viruses, such as the lack of biomarkers
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Combining Oncolytic Viruses with Chimeric Antigen Receptor T Cell Therapy Hum. Gene Ther. (IF 4.273) Pub Date : 2021-02-16 Kyle McGrath; Gianpietro Dotti
Chimeric antigen receptor (CAR) T cell therapy has revolutionized the treatment of hematological malignancies, but solid tumors continue to pose significant challenges. Oncolytic viruses (OVs) have generated significant excitement in the field of cancer treatment recently. In particular, OVs can help CAR T cells overcome some of the immunosuppressive mechanisms within the tumor microenvironment through
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Real-Time Visualization and Quantification of Oncolytic M1 Virus In Vitro and In Vivo Hum. Gene Ther. (IF 4.273) Pub Date : 2021-02-16 Wenbo Zhu; Jiankai Liang; Jingyi Tan; Li Guo; Jing Cai; Jun Hu; Guangmei Yan; Yang Liu; Jiayu Zhang; Deli Song; Jia Dan; Chun-Wa Wong; Xingwen Su; Pengxin Qiu; Yuan Lin
Alphavirus M1 is a promising oncolytic virus for cancer therapy. Here, we constructed a fluorescent reporter virus for real-time visualization and quantification of M1 virus both in vitro and in vivo. The reporter-encoding M1 virus maintained the characteristics of parental virus in the aspects of structure, replication capacity, the feature to induce cytopathic cell death, and the property of tumor
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A Novel Imaging Approach for Single-Cell Real-Time Analysis of Oncolytic Virus Replication and Efficacy in Cancer Cells Hum. Gene Ther. (IF 4.273) Pub Date : 2021-02-16 Lorraine Quillien; Sokunthea Top; Sandrine Kappler-Gratias; Agathe Redouté; Nelson Dusetti; Charlotte Quentin-Froignant; Hubert Lulka; Christelle Camus-Bouclainville; Louis Buscail; Franck Gallardo; Stéphane Bertagnoli; Pierre Cordelier
Oncolytic viruses (OVs) are novel cancer gene therapies that are moving toward the forefront of modern medicines. However, their full therapeutic potential is hindered by the lack of convenient and reliable strategies to visualize and quantify OV growth kinetics and therapeutic efficacy in live cells. In this study, we present an innovative imaging approach for single-cell real-time analysis of OV
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Oncolytic Adenovirus ORCA-010 Activates Proinflammatory Myeloid Cells and Facilitates T Cell Recruitment and Activation by PD-1 Blockade in Melanoma Hum. Gene Ther. (IF 4.273) Pub Date : 2021-02-16 Ioanna Milenova; Marta Lopez Gonzalez; Dafne C.A. Quixabeira; Joao Manuel Santos; Victor Cervera-Carrascon; Wenliang Dong; Akseli Hemminki; Victor W. van Beusechem; Rieneke van de Ven; Tanja D. de Gruijl
Immune checkpoint inhibitors have advanced the treatment of melanoma. Nevertheless, a majority of patients are resistant, or develop resistance, to immune checkpoint blockade, which may be related to prevailing immune suppression by myeloid regulatory cells in the tumor microenvironment (TME). ORCA-010 is a novel oncolytic adenovirus that selectively replicates in, and lyses, cancer cells. We previously
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Oncolytic Adenovirus Type 3 Coding for CD40L Facilitates Dendritic Cell Therapy of Prostate Cancer in Humanized Mice and Patient Samples Hum. Gene Ther. (IF 4.273) Pub Date : 2021-02-16 Sadia Zafar; Saru Basnet; Inga-Maria Launonen; Dafne Carolina Alves Quixabeira; Joao Santos; Otto Hemminki; Minna Malmstedt; Victor Cervera-Carrascon; Pasi Aronen; Riikka Kalliokoski; Riikka Havunen; Antti Rannikko; Tuomas Mirtti; Mika Matikainen; Anna Kanerva; Akseli Hemminki
Dendritic cell (DC)-based vaccines have shown some degree of success for the treatment of prostate cancer (PC). However, the highly immunosuppressive tumor microenvironment leads to DC dysfunction, which has limited the effectiveness of these vaccines. We hypothesized that use of a fully serotype 3 oncolytic adenovirus (Ad3-hTERT-CMV-hCD40L; TILT-234) could stimulate DCs in the prostate tumor microenvironment
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Oncolytic Herpes Simplex Virus Type 2 Can Effectively Inhibit Colorectal Cancer Liver Metastasis by Modulating the Immune Status in the Tumor Microenvironment and Inducing Specific Antitumor Immunity Hum. Gene Ther. (IF 4.273) Pub Date : 2021-02-16 Wen Zhang; Beibei Zeng; Xiao Hu; Lingjie Zou; Jing Liang; Yan Song; Binlei Liu; Shangmei Liu
Although colorectal cancer is the leading cause of death in patients with liver metastases, there are no efficient treatments available. Oncolytic virus therapy, a new type of tumor therapy, has become a potential solution. With the goal of improving the treatment of advanced colorectal cancer, we applied oncolytic herpes simplex virus type 2 (oHSV2) in a mouse model of colorectal cancer with liver
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miR-375- and miR-1-Regulated Coxsackievirus B3 Has No Pancreas and Heart Toxicity But Strong Antitumor Efficiency in Colorectal Carcinomas Hum. Gene Ther. (IF 4.273) Pub Date : 2021-02-16 Ahmet Hazini; Babette Dieringer; Markian Pryshliak; Klaus-Peter Knoch; Lisanne Heimann; Beatrice Tolksdorf; Kathleen Pappritz; Muhammad El-Shafeey; Michele Solimena; Antje Beling; Jens Kurreck; Karin Klingel; Henry Fechner
Coxsackievirus B3 (CVB3) has strong oncolytic activity in colorectal carcinoma but it also infects the pancreas and the heart. To improve the safety of the virus, here we investigated whether pancreas and cardiac toxicity can be prevented by insertion of target sites (TS), which are complementary to miR-375 and miR-1 into the viral genome. Although miR-375 and miR-1 are abundantly expressed in the
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Gene Therapy in a Mouse Model of Niemann–Pick Disease Type C1 Hum. Gene Ther. (IF 4.273) Pub Date : 2021-02-22 Yoshie Kurokawa; Hitoshi Osaka; Takeshi Kouga; Eriko Jimbo; Kazuhiro Muramatsu; Sachie Nakamura; Yuki Takayanagi; Tatsushi Onaka; Shin-ichi Muramatsu; Takanori Yamagata
Niemann–Pick disease type C1 (NPC1) is a fatal congenital neurodegenerative disorder caused by mutations in the NPC1 gene, which is involved in cholesterol transport in lysosomes. Broad clinical manifestations of NPC1 include liver failure, pulmonary disorder, neurological deficits, and psychiatric symptoms. The main cause of death in NPC1 patients involves central nervous system (CNS) dysfunction;
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Feasibility of Bone Marrow Mesenchymal Stem Cell-Mediated Synthetic Radiosensitive Promoter-Combined Sodium Iodide Symporter for Radiogenetic Ovarian Cancer Therapy Hum. Gene Ther. (IF 4.273) Pub Date : 2021-02-22 Shuo Shi; Fei Li; Liangcai Wu; Liwei Zhang; Lei Liu
Ovarian cancer is the most lethal gynecological cancer, most patients relapse within 12–24 months, and eventually die, especially platinum-resistant patients. Gene therapy has been one of the most potential methods for tumor treatment. Bone marrow mesenchymal stem cells (BMSCs) have been used for systemic delivery of therapeutic genes to solid tumors. Sodium iodide symporter (NIS) is an intrinsic membrane
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Design and Assessment of Novel Anti-CD30 Chimeric Antigen Receptors with Human Antigen-Recognition Domains Hum. Gene Ther. (IF 4.273) Pub Date : 2021-02-22 Stephanie Choi; Melissa A. Pegues; Norris Lam; Claudia Geldres; Danielle Vanasse; James N. Kochenderfer
Chimeric antigen receptors (CARs) are artificial fusion proteins that incorporate antigen-recognition domains and T cell signaling domains. CD30 is a cell surface protein expressed on Hodgkin's lymphoma, some T cell lymphomas, and some B cell lymphomas. CD30 has a restricted expression pattern in normal cells, so CD30 has good potential as a clinical target for CAR T cells. We compared three different
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AAV1-Mediated shRNA Knockdown of SASH1 in Rat Bronchus Attenuates Hypoxia-Induced Pulmonary Artery Remodeling Hum. Gene Ther. (IF 4.273) Pub Date : 2021-02-22 Hong Liu; Ning Wang; Jun Li; Wenting Wang; Wei Han; Qinghai Li
Pulmonary hypertension (PH) is a proliferative disease characterized by pulmonary arterial remodeling (PAR). SAM and SH3 domain containing 1 (SASH1) is a novel tumor suppressor gene whose biological function in PH is unclear. In this study, a hypoxia-induced pulmonary hypertension (HPH) rat model was constructed to explore the role of SASH1 in PAR. Histopathological changes in the lung tissue and hemodynamic
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Rational Selection of CRISPR-Cas Triggering Homology-Directed Repair in Human Cells Hum. Gene Ther. (IF 4.273) Pub Date : 2021-02-22 Fanfan Li; Chenchen Zhou; Tianxiang Tu; Yuanyuan Liu; Xiujuan Lv; Bang Wang; Zongming Song; Qifeng Zhao; Changbao Liu; Feng Gu; Junzhao Zhao
The CRISPR (clustered regularly interspaced short palindromic repeat)-Cas (CRISPR-associated) nucleases have been widely applied for genome engineering. Cas9 (Streptococcus pyogenes Cas9 [SpCas9] and Staphylococcus aureus Cas9 [SaCas9]) and Cpf1 (i.e., Francisella novicida U112 Cpf1 [FnCpf1], also named FnCas12a) were harnessed to perform gene editing in human cells. Precise genetic modification by
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Systemic scAAV9.U1a.hSGSH Delivery Corrects Brain Biochemistry in Mucopolysaccharidosis Type IIIA at Early and Later Stages of Disease Hum. Gene Ther. (IF 4.273) Pub Date : 2021-02-22 Jennifer T. Saville; Ainslie L.K. Derrick-Roberts; Chantelle McIntyre; Maria Fuller
Mucopolysaccharidosis type IIIA (MPS IIIA, Sanfilippo A syndrome) is a single gene (SGSH) childhood onset neurodegenerative disease for which gene therapy is in clinical trial. Theoretically, the transfer of a working gene should enable functional expression of the defective protein and rescue the phenotype when administered before the onset of irreversible disease. Recombinant adeno-associated virus
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Gene Therapy as an Emerging Therapeutic Approach to Breast Cancer: New Developments and Challenges Hum. Gene Ther. (IF 4.273) Pub Date : 2021-02-18 Motahareh Sheikh-Hosseini; Bagher Larijani; Zahra Gholipoor Kakroodi; Mahshid Shokoohi; Mohammad Moarefzadeh; Forough Azam Sayahpour; Parisa Goodarzi; Babak Arjmand
Breast cancer is a heterogeneous disease, which is the consequence of several genetic and environmental factors. Also, it is one of the most common causes of cancer death and second leading cancer among women all around the world. Therefore, it is necessary to develop novel therapeutic approaches useful for the successful treatment of breast cancer. As conventional treatments had limited success, alternative
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Clinical Course and Risk Factors of Disease Deterioration in Critically Ill Patients with COVID-19 Hum. Gene Ther. (IF 4.273) Pub Date : 2021-02-18 Weidong Qin; Wenwu Bai; Keyin Liu; Ya Liu; Xiao Meng; Kai Zhang; Mingxiang Zhang
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) began in December 2019 and rapidly spread to other provinces in China as well as other countries. In this study, 262 patients diagnosed with moderate to severe SARS-CoV-2 pneumonia in Wuhan, China, were analyzed. Data were compared between survivors and nonsurvivors. Of all the 262 patients, 23 (8.8%) patients died and 239 (91.2%) were
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Adeno-Associated Virus-Mediated Gene Therapy in the Mashlool, Atp1a3Mashl/+, Mouse Model of Alternating Hemiplegia of Childhood Hum. Gene Ther. (IF 4.273) Pub Date : 2021-02-12 Arsen S. Hunanyan; Boris Kantor; Ram S. Puranam; Courtney Elliott; Angela McCall; Justin Dhindsa; Promila Pagadala; Keri Wallace; Jordan Poe; Talha Gunduz; Aravind Asokan; Dwight D. Koeberl; Mai K. ElMallah; Mohamad A. Mikati
Alternating Hemiplegia of Childhood (AHC) is a devastating autosomal dominant disorder caused by ATP1A3 mutations, resulting in severe hemiplegia and dystonia spells, ataxia, debilitating disabilities, and premature death. Here, we determine the effects of delivering an extra copy of the normal gene in a mouse model carrying the most common mutation causing AHC in humans, the D801N mutation. We used
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pNaSS-Grafted PCL Film-Guided rAAV TGF-β Gene Therapy Activates the Chondrogenic Activities in Human Bone Marrow Aspirates Hum. Gene Ther. (IF 4.273) Pub Date : 2021-02-11 Dr. Jagadeesh Kumar Venkatesan; Dr. Xiaoyu Cai; Dr. Weikun Meng; Dr. Ana Rey-Rico; Miss Gertrud Schmitt; Mrs. Susanne Speicher-Mentges; Dr. Céline Falentin-Daudré; Dr. Amélie Leroux; Prof. Henning Madry; Véronique Migonney; Prof. Magali Cucchiarini
Scaffold-guided viral gene therapy is a novel, powerful tool to enhance the processes of tissue repair in articular cartilage lesions via the delivery and overexpression of therapeutic genes in a non-invasive, controlled release manner based on a procedure that may protect the gene vehicles from undesirable host immune responses. In the present study, we examined the potential of transferring a recombinant
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Optimised protocol for accurate titration of AAV vectors Hum. Gene Ther. (IF 4.273) Pub Date : 2021-02-09 Ms. Tuisku Suoranta; Nihay Laham-Karam; Prof. Seppo Ylä-Herttuala
Adeno-associated virus (AAV) is currently the most popular gene delivery vector for in vivo gene therapy. However, variability in titration methods between different laboratories affects the reproducibility of experiments and evaluation of safety and efficacy in clinical trials. We describe an optimised protocol for AAV titration, including qPCR standard preparation and quantitation and treatment of
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Single-use capture purification of adeno-associated viral gene transfer vectors by membrane-based steric exclusion chromatography Hum. Gene Ther. (IF 4.273) Pub Date : 2021-02-06 Mr. Pavel Marichal-Gallardo; Dr. Kathleen Börner; Dr. Michael Martin Pieler; Ms. Vera Sonntag-Buck; Dr. Martin Obr; Mr. David Bejarano; Prof. Michael Werner Wolff; Prof. Hans-Georg Kräusslich; Prof. Udo Reichl; Dr. Dirk Grimm
We present membrane-based steric exclusion chromatography (SXC) as a universal capture step for purification of adeno-associated virus (AAV) gene transfer vectors independent of their serotype and surface characteristics. SXC is performed by mixing an unpurified cell culture supernatant containing AAV particles with polyethylene glycol (PEG) and feeding the mixture onto a chromatography filter unit
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Characterization and Functional Analysis of CD44v6.CAR T Cells Endowed with a New LNGFR-based Spacer Hum. Gene Ther. (IF 4.273) Pub Date : 2021-02-06 Dr. Anna Stornaiuolo; Dr. Barbara Valentinis; Dr. Camilla Sirini; Dr. Cinzia Scavullo; Dr. Claudia Asperti; Dr. Dan Zhou; Dr. Yeny Martinez De La Torre; Dr. Stefano Corna; Dr. Monica Casucci; Dr. Simona Porcellini; Dr. Catia Traversari
Effectiveness of adoptively transferred chimeric antigen receptor (CAR) T cells strongly depends on the quality of CAR-mediated interaction of the effector cells with the target antigen on tumor cells. A major role in this interaction is played by the affinity of the scFv for the antigen, and by the CAR design. In particular, the spacer domain may impact on the CAR T cell function by affecting the
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The Challenge of Gene Therapy for Neurological Diseases: Strategies and Tools to Achieve Efficient Delivery to the Central Nervous System Hum. Gene Ther. (IF 4.273) Pub Date : 2021-01-26 Françoise Piguet; Timothée de Saint Denis; Emilie Audouard; Kevin Beccaria; Arthur André; Guillaume Wurtz; Raphael Schatz; Sandro Alves; Caroline Sevin; Michel Zerah; Nathalie Cartier
For more than 10 years, gene therapy for neurological diseases has experienced intensive research growth and more recently therapeutic interventions for multiple indications. Beneficial results in several phase 1/2 clinical studies, together with improved vector technology have advanced gene therapy for the central nervous system (CNS) in a new era of development. Although most initial strategies have
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Linking the Expression of Therapeutic Genes to Unfolded Protein Response: A New Option for Anti-Hepatitis B Virus Gene Therapy Hum. Gene Ther. (IF 4.273) Pub Date : 2021-01-22 Estanislao Nistal-Villán; Josepmaria Argemi; Anchel de Jaime-Soguero; Roberto Ferrero; Marianna di Scala; Estefania Rodriguez-Garcia; Aniol Coll; Sergio Rius-Rocabert; Jesús Prieto; Gloria González-Aseguinolaza; Tomás Aragón
Tight control of transgene expression is key to ensure the efficacy of a wide range of gene therapy interventions, in which the magnitude and duration of gene expression have to be adjusted to therapeutic needs, thereby limiting secondary effects. The development of upgraded strategies to link transgene expression to pathological stress episodes is an unmet need in gene therapy. Here, we propose an
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Bone Marrow Mesenchymal Stem Cells-Derived Exosomal MicroRNA-150-3p Promotes Osteoblast Proliferation and Differentiation in Osteoporosis Hum. Gene Ther. (IF 4.273) Pub Date : 2021-01-22 Min Qiu; Shuheng Zhai; Qin Fu; Da Liu
At present, much more studies have focused on the role of microRNAs in osteoporosis, but the more specific role of microRNA-150-3p (miR-150-3p) in osteoporosis still needs full exploration. We aim at investigating the role of miR-150-3p in osteoporosis and at exploring the related mechanisms. Bone marrow mesenchymal stem cells (BMSCs) were cultured, from which exosomes were isolated. Osteoporosis models
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Association of NPC1L1 and HMGCR Gene Polymorphisms with Major Adverse Cardiac and Cerebrovascular Events in Patients with Three-Vessel Disease Hum. Gene Ther. (IF 4.273) Pub Date : 2021-01-22 Xueyan Zhao; Jiawen Li; Xiaofang Tang; Ru Liu; Jingjing Xu; Lianjun Xu; Lin Jiang; Keyong Huang; Jian Tian; Xinxing Feng; Yajie Wu; Yin Zhang; Dong Wang; Kai Sun; Bo Xu; Wei Zhao; Rutai Hui; Runlin Gao; Lei Song; Jinqing Yuan
Three-vessel disease (TVD) is a severe coronary heart disease (CHD) with poor prognosis. Niemann-Pick C1-like 1 (NPC1L1) is a transporter protein for exogenous cholesterol absorption, and 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) is a rate-limiting enzyme for cholesterol synthesis. We aimed to investigate the association between NPC1L1 and HMGCR gene polymorphisms and major adverse cardiac
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Capillary Electrophoresis-Sodium Dodecyl Sulfate with Laser-Induced Fluorescence Detection As a Highly Sensitive and Quality Control-Friendly Method for Monitoring Adeno-Associated Virus Capsid Protein Purity Hum. Gene Ther. (IF 4.273) Pub Date : 2021-01-22 Zichuan Zhang; Jeehae Park; Hannah Barrett; Scott Dooley; Claire Davies; Marc F. Verhagen
The capsid protein purity of adeno-associated virus (AAV) is considered a critical quality attribute of AAV-based gene therapy products. However, the analytical methods currently available to monitor the viral capsid proteins, which are present in extremely low concentrations, have limited sensitivity and robustness, thus limiting their general applicability. As a result, there is an urgent need to
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AAV Jude: An Interview with R. Jude Samulski Hum. Gene Ther. (IF 4.273) Pub Date : 2021-01-18 Kevin Davies
Editor's note:It is rare that a breakthrough study performed as a graduate student sets the course for the rest of a scientist's distinguished career. But Richard Jude Samulski's study in the early 1980s on an emerging viral vector—adeno-associated virus (AAV)—played a profound role in shaping the evolution of the gene therapy field. Samulski et al. stuck to their beliefs in the clinical potential
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Engaging cell and gene therapists in HIV cure. Hum. Gene Ther. (IF 4.273) Pub Date : 2021-01-18 Rowena Johnston
Cell and gene therapy (CGT) has a variety of potential applications in HIV prevention and management. Bibliometric and network analyses suggest potential points of entry for gene therapists into HIV cure research. The existing network of CGT researchers for HIV cure will benefit from an influx of fresh ideas and energy from CGT researchers keen to embrace a new challenge for an old virus.
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Safe and Effective In Vivo Targeting and Gene Editing in Hematopoietic Stem Cells: Strategies for Accelerating Development Hum. Gene Ther. (IF 4.273) Pub Date : 2021-01-18 Paula Cannon; Aravind Asokan; Agnieszka Czechowicz; Paula Hammond; Donald B. Kohn; Andre Lieber; Punam Malik; Peter Marks; Matthew Porteus; Els Verhoeyen; Drew Weissman; Irving Weissman; Hans-Peter Kiem
On May 11, 2020, the National Institutes of Health (NIH) and the Bill & Melinda Gates Foundation (Gates Foundation) held an exploratory expert scientific roundtable to inform an NIH–Gates Foundation collaboration on the development of scalable, sustainable, and accessible HIV and sickle cell disease (SCD) therapies based on in vivo gene editing of hematopoietic stem cells (HSCs). A particular emphasis
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Gene editing for the treatment of Primary Immunodeficiency Diseases. Hum. Gene Ther. (IF 4.273) Pub Date : 2021-01-18 Rajeev Rai,Adrian J Thrasher,Alessia Cavazza
With conventional treatments for primary immunodeficiency diseases (PIDs), such as allogeneic stem cell transplantation or autologous gene therapy, still facing important challenges, the rapid development of genome editing technologies to more accurately correct the mutations underlying the onset of genetic disorders has provided a new alternative, yet promising platform for the treatment of such diseases
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HIV Gene Therapy: An Update Hum. Gene Ther. (IF 4.273) Pub Date : 2021-01-18 Tatjana I. Cornu; Claudio Mussolino; Matthias C. Müller; Claudia Wehr; Winfried V. Kern; Toni Cathomen
Progress in antiretroviral therapy has considerably reduced mortality and notably improved the quality of life of individuals infected with HIV since the pandemic began some 40 years ago. However, drug resistance, treatment-associated toxicity, adherence to medication, and the need for lifelong therapy have remained major challenges. While the development of an HIV vaccine has remained elusive, considerable
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Conditioning regimens in long term nonclinical studies to support development of ex-vivo gene therapy: review of non-proliferative and proliferative changes. Hum. Gene Ther. (IF 4.273) Pub Date : 2021-01-18 Franck Chanut,Francesca Sanvito,Giuliana Ferrari,Ilaria Visigalli,Nicola Carriglio,Raisa Jofra Hernandez,Rossana Norata,Claudio Doglioni,Luigi Naldini,Patrizia Cristofori
Hematopoietic stem cell gene therapy has become a successful therapeutic strategy for some inherited genetic disorders. Pre-clinical toxicity studies performed to support the human clinical trials using viral-mediated gene transfer and autologous hematopoietic stem and progenitor cell (HSPC) transplantation are complex and the use of mouse models of human diseases makes interpretation of the results
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Knockout-Induced Pluripotent Stem Cells for Disease and Therapy Modeling of IL-10-Associated Primary Immunodeficiencies Hum. Gene Ther. (IF 4.273) Pub Date : 2021-01-18 Johanna Sens; Dirk Hoffmann; Lucas Lange; Philippe Vollmer Barbosa; Michael Morgan; Christine S. Falk; Axel Schambach
Samples from patients with rare diseases, such as primary immunodeficiencies, are often limited, which hampers careful analysis of the pathomechanisms involved in immune cell dysregulation. To overcome this issue, induced pluripotent stem cells (iPSCs) represent an almost inexhaustible cell source and thus provide an excellent opportunity to generate disease models for rare diseases and to validate
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Gene Transfer in Adeno-Associated Virus Seropositive Rhesus Macaques Following Rapamycin Treatment and Subcutaneous Delivery of AAV6, but Not Retargeted AAV6 Vectors Hum. Gene Ther. (IF 4.273) Pub Date : 2021-01-18 Daniel Stone; Elizabeth J. Kenkel; Michelle A. Loprieno; Motoko Tanaka; Harshana S. De Silva Feelixge; Arjun J. Kumar; Laurence Stensland; Willimark M. Obenza; Solomon Wangari; Chul Y. Ahrens; Robert D. Murnane; Christopher W. Peterson; Hans-Peter Kiem; Meei-Li Huang; Martine Aubert; Shiu-Lok Hu; Keith R. Jerome
Adeno-associated virus (AAV) vectors such as AAV6, which shows tropism for primary human CD4+ T cells in vitro, are being explored for delivery of anti-HIV therapeutic modalities in vivo. However, pre-existing immunity and sequestration in nontarget organs can significantly hinder their performance. To overcome these challenges, we investigated whether immunosuppression would allow gene delivery by
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In Vivo Gene Therapy for Canine SCID-X1 Using Cocal-Pseudotyped Lentiviral Vector. Hum. Gene Ther. (IF 4.273) Pub Date : 2021-01-18 Yogendra S Rajawat,Olivier Humbert,Savannah M Cook,Stefan Radtke,Dnyanada Pande,Mark Enstrom,Martin E Wohlfahrt,Hans-Peter Kiem
Hematopoietic stem and progenitor cell (HSPC)-based ex vivo gene therapy has demonstrated clinical success for X-linked severe combined immunodeficiency (SCID-X1) patients who lack a suitable donor for HSPC transplantation. Nevertheless, this form of treatment is associated with an increased risk of infectious disease complications and genotoxicity mainly due to the conditioning regimen. In addition
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Nuclease-deficient CRISPR-based approaches for in vitro and in vivo gene activation Hum. Gene Ther. (IF 4.273) Pub Date : 2021-01-15 Dr. Angela Lek; Mr. Kaiyue Ma; Dr. Keryn Woodman; Dr. Monkol Lek
CRISPR-based technology has been adapted to achieve a wide range of genome modifications including transcription regulation. The focus of this review is on the application of CRISPR-based platforms such as nuclease-deficient Cas9 and Cas12a, to achieve targeted gene activation. We review studies to date that have employed CRISPR-based activation technology for the elucidation of biological mechanism
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Towards human translation of lentiviral airway gene delivery for cystic fibrosis: A one-month CFTR and reporter gene study in marmosets Hum. Gene Ther. (IF 4.273) Pub Date : 2021-01-15 Dr. Nigel R Farrow; Dr. Patricia Cmielewski; Dr. Juliette Delhove; Dr. Nathan Rout-Pitt; Dr. lewis Vaughan; Dr. Tim Kuchel; Dr. Chris Christou; Dr. John Finnie; Mr. Mathew Smith; Dr. Emma Knight; Dr. Martin Donnelley; Dr. David Parsons
Gene therapy continues to be a promising contender for the treatment of cystic fibrosis (CF) airway disease. We have previously demonstrated that airway conditioning with lysophosphatidylcholine (LPC) followed by delivery of a HIV-1 based lentiviral vector (LV) functionally corrects the CF transmembrane conductance regulator (CFTR) defect in the nasal airways of CF mice. In our earlier pilot study
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Comprehensive analysis of cell therapy on chronic skin wound healing: a meta-analysis Hum. Gene Ther. (IF 4.273) Pub Date : 2021-01-15 Dr. Yujie Dong; Dr. Qi Yang; Dr. Xiaojie Sun
Wound healing has been greatly challenging in different acute and chronic skin injuries. Among them, non-revascularizable critical limb ischemic ulcers, venous leg ulcers, and diabetic lower limb or extremity ulcers are well-known refractory skin injuries that are difficult to treat. Partly differentiated progenitor cell-based graft transplantation or direct injection of autologous stem cells might
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Host immune responses after suprachoroidal delivery of AAV8 in nonhuman primate eyes. Hum. Gene Ther. (IF 4.273) Pub Date : 2021-01-15 Dr. Sook Hyun Chung; Miss Iris Natalie Mollhoff; Dr. Alaknanda Mishra; Miss Tzu-ni Sin; Miss Taylor Ngo; Dr. Thomas Ciulla; Dr. Paul A Sieving; Dr. Sara Thomasy; Dr. Glenn Yiu
The suprachoroid is a potential space located between the sclera and choroid of the eye which provides a novel route for ocular drug or viral vector delivery. Suprachoroidal injection of AAV8 using transscleral microneedles enables widespread transgene expression in eyes of nonhuman primates, but may cause intraocular inflammation. We characterized the host humoral and cellular immune responses after
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Lack of toxicity in non-human primates receiving clinically relevant doses of an AAV9.U7snRNA vector designed to induce DMD exon 2 skipping Hum. Gene Ther. (IF 4.273) Pub Date : 2021-01-06 Dr. Liubov V Gushchina; Ms. Emma C Frair; Ms. Natalie L Rohan; Ms. Adrienne J Bradley; Ms. Hemantkumar D Chavan; Dr. Hsin-Jung Chou; Ms. Michelle Eggers; Dr. Megan A Waldrop; Dr. Nicolas wein; Dr. Kevin Flanigan
Therapeutic exon skipping as a treatment for Duchenne muscular dystrophy (DMD) has largely concentrated on delivery of antisense oligomers to treat out-of-frame exon deletions. Here we report on the preclinical development of an AAV-encapsidated viral vector containing four copies of the non-coding U7 small nuclear RNA (U7snRNA), each targeted to either the splice donor or the splice acceptor sites
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Detailed Protocol for the Novel and Scalable Viral Vector Upstream Process for AAV Gene Therapy Manufacturing Hum. Gene Ther. (IF 4.273) Pub Date : 2021-01-04 Dr. Nagarathinam Selvaraj; Dr. Chao-Kuei Wang; Dr. Brian Bowser; Dr. Trevor L Broadt; Mr. Samir Shaban; Ms. Jenna Burns; Dr. Nirmala Saptharishi; Dr. Peter Pechan; Mrs. Diane Golebiowski; Dr. Asaf Alimardanov; Dr. Nora N. Yang; Dr. George Mitra; Dr. Ramarao Vepachedu
Recombinant adeno-associated viral (rAAV) vector-based gene therapy has been adapted for use in more than 100 clinical trials. This is mainly because of its excellent safety profile, ability to target a wide range of tissues, stable transgene expression, and significant clinical benefit. However, the major challenge is to produce a high titer, high potency vector to achieve a better therapeutic effect
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Safety of Direct Intraparenchymal AAVrh.10-mediated CNS Gene Therapy for Metachromatic Leukodystrophy Hum. Gene Ther. (IF 4.273) Pub Date : 2020-12-30 Dr. Jonathan B Rosenberg; Mr. Alvin Chen; Dr. Bishnu P De; Dr. Jonathan Dyke; Dr. Douglas Ballon; Dr. Sebastien Monette; Dr. Rodolfo Ricart Arbona; Dr. Stephen M. Kaminsky; Dr. Ronald G Crystal; Dr. Dolan Sondhi
Metachromatic leukodystrophy (MLD), a fatal pediatric neurodegenerative lysosomal storage disease caused by mutations in the arylsulfatase A (ARSA) gene, is characterized by intracellular accumulation of sulfatides in the lysosomes of cells of the central nervous system (CNS). In previous studies, we have demonstrated efficacy of AAVrh.10hARSA, an adeno-associated virus (AAV) serotype rh.10 vector
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Efficacy and Safety of Clinical Grade hVEGF-DΔNΔC Gene Therapy Containing Residual Replication-Competent Adenoviruses Hum. Gene Ther. (IF 4.273) Pub Date : 2020-12-28 Dr. Aleksi Johannes Leikas; Nihay Laham-Karam; Ms. Eline Agtereek; Dr. Hanna Marjaana Peltonen; Mr. Tuomas Selander; Dr. Petra Korpisalo; Mr. Lari Holappa; Prof. Juha EK Hartikainen; Mr. Tommi Heikura; Prof. Seppo Ylä-Herttuala
Biological bypass via induced angiogenesis by vascular endothelial growth factor D (VEGF-D) gene therapy is a new concept for the treatment of cardiac ischemia. Serotype 5 adenoviruses are used in the clinical trials for transferring the VEGF-D cDNA into the ischemic myocardium. However, the presence of replication-competent vectors in the adenovirus products is a widely recognized problem that may
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Central Nervous System Therapeutic Targets in Friedreich Ataxia Hum. Gene Ther. (IF 4.273) Pub Date : 2020-12-16 Ian H. Harding; David R. Lynch; Arnulf H. Koeppen; Massimo Pandolfo
Friedreich ataxia (FRDA) is an autosomal recessive inherited multisystem disease, characterized by marked differences in the vulnerability of neuronal systems. In general, the proprioceptive system appears to be affected early, while later in the disease, the dentate nucleus of the cerebellum and, to some degree, the corticospinal tracts degenerate. In the current era of expanding therapeutic discovery
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Quantitative Whole-Body Imaging of I-124-Labeled Adeno-Associated Viral Vector Biodistribution in Nonhuman Primates Hum. Gene Ther. (IF 4.273) Pub Date : 2020-12-16 Douglas J. Ballon; Jonathan B. Rosenberg; Edward K. Fung; Anastasia Nikolopoulou; Paresh Kothari; Bishnu P. De; Bin He; Alvin Chen; Linda A. Heier; Dolan Sondhi; Stephen M. Kaminsky; Paul David Mozley; John W. Babich; Ronald G. Crystal
A method is presented for quantitative analysis of the biodistribution of adeno-associated virus (AAV) gene transfer vectors following in vivo administration. We used iodine-124 (I-124) radiolabeling of the AAV capsid and positron emission tomography combined with compartmental modeling to quantify whole-body and organ-specific biodistribution of AAV capsids from 1 to 72 h following administration
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Anti-oncogenic effect of microRNA-206 on neck squamous cell carcinoma through inhibition of proliferation and promotion of apoptosis and autophagy. Hum. Gene Ther. (IF 4.273) Pub Date : 2020-12-16 Tiancheng Li,Zhien Feng,Yingyi Wang,Hong Zhang,Qian Li,Erik Schiferle,Yao Qin,Shuifang Xiao
Recent studies have reported the crucial role of stanniocalcin-2 (STC2) in hepatocellular carcinoma; however, its role in head and neck squamous cell carcinoma (HNSCC) remains elusive. In this study, microRNA-206 (miR-206) was predicted to target STC2 gene. The study herein aimed to elucidate the effect of miR-206 on HNSCC by targeting STC2. STC2 was highly expressed in HNSCC tissues and cells. By
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Long Non-coding RNA TUG1 Promotes Parkinson's Disease via Modulating MiR-152-3p/PTEN Pathway. Hum. Gene Ther. (IF 4.273) Pub Date : 2020-12-16 Kaihua Zhai,Boyu Liu,Lin Gao
Long-noncoding RNA taurine upregulated gene 1 (TUG1) participates in nervous system diseases, but its function in Parkinson's disease (PD) remains unclear. This study explored the function and mechanism of TUG1 in PD. A PD model was constructed using SH-SY5Y cells induced by 1-methyl-4-phenylpyridinium (MPP+) in vitro and mice treated by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in vivo.
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Retinal Tropism and Transduction of Adeno-Associated Virus (AAV) Varies by Serotype and Route of Delivery (Intravitreal, Subretinal or Suprachoroidal) in Rats. Hum. Gene Ther. (IF 4.273) Pub Date : 2020-12-16 Ian C Han,Justine L Cheng,Erin Burnight,Christy L Ralston,Jessica L Fick,Gabriella J Thomsen,Emilio F Tovar,Stephen Russell,Elliott H Sohn,Robert F Mullins,Edwin Stone,Budd A Tucker,Luke Aaron Wiley
Viral-mediated gene augmentation offers tremendous promise for the treatment of inherited retinal diseases. The development of effective gene therapy requires an understanding of the vector's tissue-specific behavior, which may vary depending on serotype, route of delivery, or target species. Using an ex vivo organotypic explant system, we previously demonstrated that retinal tropism and transduction
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Human BMSCs modified hybrid baculovirus-adeno-associated viral vectors targeting 131I therapy of hypopharyngeal carcinoma. Hum. Gene Ther. (IF 4.273) Pub Date : 2020-12-16 Jun Wang,Dedi Kong,Liying Zhu,Shili Wang,Xingmei Sun
Hypopharyngeal carcinoma is one of the most aggressive subtypes of squamous cell carcinoma of the head and neck. Although significant progress has been made in surgical techniques, radiotherapy, and chemotherapy, the prognosis is still poor. Mesenchymal stem cells (MSCs) have attracted substantial attention as tumor-targeted cellular carriers for cancer gene therapy. We have previously shown that recombinant
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Genetic Rescue of X-Linked Retinoschisis Mouse (Rs1−/y) Retina Induces Quiescence of the Retinal Microglial Inflammatory State Following AAV8-RS1 Gene Transfer and Identifies Gene Networks Underlying Retinal Recovery Hum. Gene Ther. (IF 4.273) Pub Date : 2020-12-14 Camasamudram Vijayasarathy; Yong Zeng; Matthew J. Brooks; Robert N. Fariss; Paul A. Sieving
To understand RS1 gene interaction networks in the X-linked retinoschisis (XLRS) mouse retina (Rs1−/y), we analyzed the transcriptome by RNA sequencing before and after in vivo expression of exogenous retinoschisin (RS1) gene delivered by AAV8. RS1 is a secreted cell adhesion protein that is critical for maintaining structural lamination and synaptic integrity of the neural retina. RS1 loss-of-function
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Multiple Genes Surrounding Bcl-xL, a Common Retroviral Insertion Site, Can Influence Hematopoiesis Individually or in Concert Hum. Gene Ther. (IF 4.273) Pub Date : 2020-12-07 Teng-Cheong Ha; Maike Stahlhut; Michael Rothe; Gabi Paul; Violetta Dziadek; Michael Morgan; Martijn Brugman; Boris Fehse; Olga Kustikova; Axel Schambach; Christopher Baum
Retroviral insertional mutagenesis (RIM) is both a relevant risk in gene therapy and a powerful tool for identifying genes that enhance the competitiveness of repopulating hematopoietic stem and progenitor cells (HSPCs). However, focusing only on the gene closest to the retroviral vector insertion site (RVIS) may underestimate the effects of RIM, as dysregulation of distal and/or multiple genes by
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Restoration of β-globin expression with optimally designed lentiviral vector for β-thalassemia treatment in Chinese patients Hum. Gene Ther. (IF 4.273) Pub Date : 2020-11-30 Dr. Wenjie Ouyang; Dr. Guoyi Dong; Dr. Weihua Zhao; Dr. Jing Li; Miss Ziheng Zhou; Dr. Gaohui Yang; Dr. Rongrong Liu; Dr. Yue Li; Dr. Qiaoxia Zhang; Dr. Xin Du; Prof. Haixi Sun; Prof. Ying Gu; Prof. Yongrong Lai; Prof. Sixi Liu; Prof. Chao Liu
β-thalassemia is one of the most prevalent genetic diseases worldwide. The current treatment for β-thalassemia is allogeneic hematopoietic stem cell transplantation (HSCT), which is limited due to lack of matched donors. Gene therapy has been developed as an alternative therapeutic option for transfusion-dependent β-thalassemia (TDT). However, successful gene therapy for β-thalassemia patients in China
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Engineered U7 snRNA restores correct β-globin pre-mRNA splicing in mouse βIVS2-654- thalassemic erythroid progenitor cells. Hum. Gene Ther. (IF 4.273) Pub Date : 2020-11-02 Annette d'Arqom,Tiwaporn Nualkaew,Natee Jearawiriyapaisarn,Ryszard Kole,Saovaros Svasti
Restoration of correct splicing of βIVS2-654-globin pre-mRNA was previously accomplished in erythroid cells from β-thalassemia/HbE patients by an engineered U7 small nuclear RNA (snRNA) that carried a sequence targeted to the cryptic branch point and an exonic splicing enhancer, U7.BP+623 snRNA. In this study, this approach was tested in thalassemic mice carrying the βIVS2-654 mutation. While correction
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Short Time to Market and Forward Planning Will Enable Cell Therapies to Deliver R&D Pipeline Value Hum. Gene Ther. (IF 4.273) Pub Date : 2020-11-02 Delfi Krishna; Laure Rittié; Hoang Tran; Xuan Zheng; Chia-en Chen-Rogers; Amanda McGillivray; Timothy Clay; Amol Ketkar; Joseph Tarnowski
There is considerable industry excitement about the curative potential of cell and gene therapies, but significant challenges remain in designing cost-effective treatments that are accessible globally. We have taken a modeling-based approach to define the cost and value drivers for cell therapy assets during pharmaceutical drug development. We have created a model development program for a lentiviral
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Genome-Editing Strategies for Treating Human Retinal Degenerations Hum. Gene Ther. (IF 4.273) Pub Date : 2020-11-19 Joel Quinn; Ayesha Musa; Ariel Kantor; Michelle E. McClements; Jasmina Cehajic-Kapetanovic; Robert E. MacLaren; Kanmin Xue
Inherited retinal degenerations (IRDs) are a leading cause of blindness. Although gene-supplementation therapies have been developed, they are only available for a small proportion of recessive IRD mutations. In contrast, genome editing using clustered-regularly interspaced short palindromic repeats (CRISPR) CRISPR-associated (Cas) systems could provide alternative therapeutic avenues for treating