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Molecular Therapy. Methods & Clinical Development

Annika M Frank, Christian J Buchholz
Lymphocytes have always been among the prime targets in gene therapy, even more so since chimeric antigen receptor (CAR) T cells have reached the clinic. However, other gene therapeutic approaches hold great promise as well. The first part of this review provides an overview of current strategies in lymphocyte gene therapy. The second part highlights the importance of precise gene delivery into B and T cells as well as distinct subtypes of lymphocytes. This can be achieved with lentiviral vectors (LVs) pseudotyped with engineered glycoproteins recognizing lymphocyte surface markers as entry receptors...
March 15, 2019: Molecular Therapy. Methods & Clinical Development
Yao Xiao, Kun Shi, Ying Qu, Bingyang Chu, Zhiyong Qian
In the past 10 years, with the increase of investment in clinical nano-gene therapy, there are many trials that have been discontinued due to poor efficacy and serious side effects. Therefore, it is particularly important to design a suitable gene delivery system. In this paper, we introduce the application of liposomes, polymers, and inorganics in gene delivery; also, different modifications with some stimuli-responsive systems can effectively improve the efficiency of gene delivery and reduce cytotoxicity and other side effects...
March 15, 2019: Molecular Therapy. Methods & Clinical Development
Charles Harvey Vannoy, Victoria Leroy, Qi Long Lu
Muscular dystrophy-dystroglycanopathies (MDDGs) resulting from fukutin-related protein ( FKRP ) gene mutations are rare disorders that result in a wide spectrum of clinical severity based on the age of onset, the degree of myogenic atrophy, and/or neurologic involvement. There is no cure for any of the FKRP -related disorders, and few options are available for symptom management. Herein, we examine the longitudinal effects of a dose-escalation study to evaluate the safety and therapeutic potential of FKRP gene-replacement therapy in a p...
December 14, 2018: Molecular Therapy. Methods & Clinical Development
Tahnee L Kennedy, Simon Guiraud, Ben Edwards, Sarah Squire, Lee Moir, Arran Babbs, Guy Odom, Diane Golebiowski, Joel Schneider, Jeffrey S Chamberlain, Kay E Davies
Duchenne muscular dystrophy (DMD) is an X-linked muscle-wasting disease caused by mutations in the dystrophin gene. DMD boys are wheelchair-bound around 12 years and generally survive into their twenties. There is currently no effective treatment except palliative care, although personalized treatments such as exon skipping, stop codon read-through, and viral-based gene therapies are making progress. Patients present with skeletal muscle pathology, but most also show cardiomyopathy by the age of 10. A systemic therapeutic approach is needed that treats the heart and skeletal muscle defects in all patients...
December 14, 2018: Molecular Therapy. Methods & Clinical Development
Yuqian Wang, Jichao Sha, Heng Wang, Lifeng An, Tie Liu, Lin Li
Allergic rhinitis (AR) involves antigen-specific immune-inflammation of the nasal mucosa. Classical therapy for AR targets the histamine pathway, e.g., histamine receptor blockers. Histamine H4 receptor (H4R) was suggested as a novel therapeutic target due to its wide expression on almost all immune-related cells. A 12-mer random peptide library was used to select the specific epitope of the H4R. The phage clone showing the highest degree of activation was verified and translated to the corresponding peptide...
December 14, 2018: Molecular Therapy. Methods & Clinical Development
Xufeng Luo, Dongmei Zhang, Jun Xie, Qin Su, Xing He, Ruipu Bai, Guangping Gao, Weiqing Pan
Infection with Schistosoma causes aberrant expression of host microRNAs (miRNAs), and normalizing the levels of dysregulated miRNAs can attenuate pathology. Here, we show that the host miRNA, miR-96 , is markedly upregulated during the progression of hepatic schistosomiasis. We demonstrate that elevation of miR-96 induces hepatic fibrosis in infected mice by suppressing the expression of its target gene, Smad7 . We show that infection with Schistosoma induces the expression of transforming growth factor β1 (TGF-β1), which in turn upregulates the expression of miR-96 through SMAD2/3-DROSHA-mediated post-transcriptional regulation...
December 14, 2018: Molecular Therapy. Methods & Clinical Development
Dan Wang, Li Zhong, Mengxin Li, Jia Li, Karen Tran, Lingzhi Ren, Ran He, Jun Xie, Richard P Moser, Cara Fraser, Tim Kuchel, Miguel Sena-Esteves, Terence R Flotte, Neil Aronin, Guangping Gao
Pre-existing neutralizing antibody (NAb) against adeno-associated virus (AAV) commonly found in primates is a major host barrier that can severely compromise in vivo gene transfer by AAV vectors. To achieve proof-of-concept success in clinical development of recombinant AAV (rAAV)-based in vivo gene therapy, it is crucial to consider the potential interference of NAb and to enroll serologically compatible study subjects. In this study, we report a large AAV NAb dataset comprising multiple large animal species and AAV serotypes and compare two NAb assays based on in vitro or in vivo transduction inhibition, respectively...
December 14, 2018: Molecular Therapy. Methods & Clinical Development
Jing-Fen Han, Salim S El-Amouri, Mei Dai, Phuong Cao, Dao Pan
Novel strategies are needed to solve the conundrum of achieving clinical efficacy with high vector copy numbers (VCNs) in hematopoietic stem cells (HSCs) while attempting to minimize the potential risk of oncogenesis in lentiviral vector (LV)-mediated gene therapy clinical trials. We previously reported the benefits of reprogramming erythroid-megakaryocytic (EMK) cells for high-level lysosomal enzyme production with less risk of activating oncogenes in HSCs. Herein, using a murine model of mucopolysaccharidosis type I (MPS I) with a deficiency of α-L-iduronidase (IDUA), we sought to determine the transgene minimum effective doses (MEDs) in major organs, and if a transient increase of IDUA-containing red blood cells and platelets by repeated phlebotomy would provide further therapeutic benefits in diseased mice after EMK-restricted LV-mediated gene therapy...
December 14, 2018: Molecular Therapy. Methods & Clinical Development
Zekun Wang, Fang Cheng, John F Engelhardt, Ziying Yan, Jianming Qiu
Human bocavirus 1 (HBoV1), an autonomous parvovirus, is a helper virus supporting replication of wild-type adeno-associated virus 2 (AAV2). In this study, we compared the helper functions from HBoV1 with those from adenovirus (Ad) for the production of recombinant AAV (rAAV) vector in HEK293 cells. We demonstrated that triple plasmids transfection of (1) a cloned HBoV1 helper minigenome (pBocaHelper) that expresses HBoV1 genes NP1 , NS2 , and BocaSR, (2) pAAV transfer plasmid, and (3) pAAVRepCap supports rAAV production in HEK293 cells...
December 14, 2018: Molecular Therapy. Methods & Clinical Development
Luis Quintino, Angrit Namislo, Marcus Davidsson, Ludivine S Breger, Patrick Kavanagh, Martino Avallone, Erika Elgstrand-Wettergren, Christina Isaksson, Cecilia Lundberg
Regulation of therapeutic transgene expression can increase the safety of gene therapy interventions, especially when targeting critical organs such as the brain. Although several gene expression systems have been described, none of the current systems has the required safety profile for clinical applications. Our group has previously adapted a system for novel gene regulation based on the destabilizing domain degron technology to successfully regulate glial cell-line derived neurotrophic factor in the brain (GDNF-F-DD)...
December 14, 2018: Molecular Therapy. Methods & Clinical Development
Maria Rosa Lidonnici, Ylenia Paleari, Francesca Tiboni, Giacomo Mandelli, Claudia Rossi, Michela Vezzoli, Annamaria Aprile, Carsten Werner Lederer, Alessandro Ambrosi, Franck Chanut, Francesca Sanvito, Andrea Calabria, Valentina Poletti, Fulvio Mavilio, Eugenio Montini, Luigi Naldini, Patrizia Cristofori, Giuliana Ferrari
Gene therapy clinical trials require rigorous non-clinical studies in the most relevant models to assess the benefit-to-risk ratio. To support the clinical development of gene therapy for β-thalassemia, we performed in vitro and in vivo studies for prediction of safety. First we developed newly GLOBE-derived vectors that were tested for their transcriptional activity and potential interference with the expression of surrounding genes. Because these vectors did not show significant advantages, GLOBE lentiviral vector (LV) was elected for further safety characterization...
December 14, 2018: Molecular Therapy. Methods & Clinical Development
Michelle Levene, Dario Pacitti, Charlotte Gasson, Jamie Hall, Marcia Sellos-Moura, Bridget E Bax
Erythrocyte encapsulated thymidine phosphorylase is recombinant Escherichia coli thymidine phosphorylase encapsulated within human autologous erythrocytes and is under development as an enzyme replacement therapy for the ultra-rare inherited metabolic disorder mitochondrial neurogastrointestinal encephalomyopathy. This study describes the method validation of a two-step bridging electrochemiluminescence immunoassay for the detection of anti-thymidine phosphorylase antibodies in human serum according to current industry practice and regulatory guidelines...
December 14, 2018: Molecular Therapy. Methods & Clinical Development
Kenneth Cornetta, Lisa Duffy, Steven A Feldman, Crystal L Mackall, Marco L Davila, Kevin J Curran, Richard P Junghans, Jean Yuh Tang, James N Kochenderfer, Roisin O'Cearbhaill, Gary Archer, Hans-Peter Kiem, Nirali N Shah, Cindy Delbrook, Rosie Kaplan, Renier J Brentjens, Isabelle Rivière, Michel Sadelain, Steven A Rosenberg
Replication-competent retrovirus (RCR) is a safety concern for individuals treated with retroviral gene therapy. RCR detection assays are used to detect RCR in manufactured vector, transduced cell products infused into research subjects, and in the research subjects after treatment. In this study, we reviewed 286 control (n = 4) and transduced cell products (n = 282) screened for RCR in the National Gene Vector Biorepository. The transduced cell samples were submitted from 14 clinical trials. All vector products were previously shown to be negative for RCR prior to use in cell transduction...
September 21, 2018: Molecular Therapy. Methods & Clinical Development
Ryo Ikeue, Aki Nakamura-Takahashi, Yuko Nitahara-Kasahara, Atsushi Watanabe, Takashi Muramatsu, Toru Sato, Takashi Okada
Hypophosphatasia is an inherited disease caused by mutations in the gene encoding tissue-nonspecific alkaline phosphatase (TNALP), the major symptom of which is hypomineralization of the bones and teeth. We had recently demonstrated that TNALP-deficient ( Akp2 -/- ) mice, which mimic the phenotype of the severe infantile form of hypophosphatasia, can be treated by intramuscular injection of a self-complementary (sc) type 8 recombinant adeno-associated virus (rAAV8) vector expressing bone-targeted TNALP with deca-aspartates at the C terminus (TNALP-D10 ) via the muscle creatine kinase (MCK) promoter...
September 21, 2018: Molecular Therapy. Methods & Clinical Development
Monir Shababi, Eric Villalón, Kevin A Kaifer, Vince DeMarco, Christian L Lorson
Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is an infantile autosomal recessive disease caused by the loss of the ubiquitously expressed IGHMBP2 gene. SMARD1 causes degeneration of alpha-motor neurons, resulting in distal muscle weakness, diaphragm paralysis, and respiratory malfunction. We have reported that delivery of a low dose of AAV9- IGHMBP2 to the CNS results in a significant rescue of the SMARD1 mouse model ( nmd ). To examine how a delivery route can impact efficacy, a direct comparison of intravenous (IV) and intracerebroventricular (ICV) delivery of AAV9- IGHMBP2 was performed...
September 21, 2018: Molecular Therapy. Methods & Clinical Development
Marianne Delville, Tayebeh Soheili, Florence Bellier, Amandine Durand, Adeline Denis, Chantal Lagresle-Peyrou, Marina Cavazzana, Isabelle Andre-Schmutz, Emmanuelle Six
Lentiviral vectors have emerged as an efficient, safe therapeutic tool for gene therapy based on hematopoietic stem cells (HSCs) or T cells. However, the monitoring of transduced cells in preclinical models remains challenging because of the inefficient transduction of murine primary T cells with lentiviral vectors, in contrast to gammaretroviral vectors. The use of this later in preclinical proof of concept is not considered as relevant when a lentiviral vector will be used in a clinical trial. Hence, there is an urgent need to develop an efficient transduction protocol for murine cells with lentiviral vectors...
September 21, 2018: Molecular Therapy. Methods & Clinical Development
Haiyan Fu, Kim Zaraspe, Naoko Murakami, Aaron S Meadows, Ricardo J Pineda, Douglas M McCarty, Joseph Muenzer
No treatment is available to address the neurological need and reversibility of MPS II. We developed a scAAV9-h IDS vector to deliver the human iduronate-2-sulfatase gene and test it in mouse model. We treated MPS II mice at different disease stages with an intravenous injection of scAAV9-mCMV-h IDS at different doses. The treatments led to rapid and persistent restoration of IDS activity and the reduction of glycosaminoglycans (GAG) throughout the CNS and somatic tissues in all cohorts. Importantly, the vector treatment at up to age 6 months improved behavior performance in the Morris water maze and normalized the survival...
September 21, 2018: Molecular Therapy. Methods & Clinical Development
Nikoletta Psatha, Andreas Reik, Susan Phelps, Yuanyue Zhou, Demetri Dalas, Evangelia Yannaki, Dana N Levasseur, Fyodor D Urnov, Michael C Holmes, Thalia Papayannopoulou
In the present report, we carried out clinical-scale editing in adult mobilized CD34+ hematopoietic stem and progenitor cells (HSPCs) using zinc-finger nuclease-mediated disruption of BCL11a to upregulate the expression of γ-globin (fetal hemoglobin). In these cells, disruption of the erythroid-specific enhancer of the BCL11A gene increased endogenous γ-globin expression to levels that reached or exceeded those observed following knockout of the BCL11A coding region without negatively affecting survival or in vivo long-term proliferation of edited HSPCs and other lineages...
September 21, 2018: Molecular Therapy. Methods & Clinical Development
Maha Tijani, Altar M Munis, Christopher Perry, Khaled Sanber, Marta Ferraresso, Tarit Mukhopadhyay, Michael Themis, Ilaria Nisoli, Giada Mattiuzzo, Mary K Collins, Yasuhiro Takeuchi
Retroviral and lentiviral vectors often use the envelope G protein from the vesicular stomatitis virus Indiana strain (VSVind.G). However, lentivector producer cell lines that stably express VSVind.G have not been reported, presumably because of its cytotoxicity, preventing simple scale-up of vector production. Interestingly, we showed that VSVind.G and other vesiculovirus G from the VSV New Jersey strain (VSVnj), Cocal virus (COCV), and Piry virus (PIRYV) could be constitutively expressed and supported lentivector production for up to 10 weeks...
September 21, 2018: Molecular Therapy. Methods & Clinical Development
Jérôme Denard, Jérémy Rouillon, Thibaut Leger, Camille Garcia, Michele P Lambert, Graziella Griffith, Christine Jenny, Jean-Michel Camadro, Luis Garcia, Fedor Svinartchouk
Under intravenous delivery, recombinant adeno-associated vectors (rAAVs) interact with blood-borne components in ways that can critically alter their therapeutic efficiencies. We have previously shown that interaction with human galectin 3 binding protein dramatically reduces rAAV-6 efficacy, whereas binding of mouse C-reactive protein improves rAAV-1 and rAAV-6 transduction effectiveness. Herein we have assessed, through qualitative and quantitative studies, the proteins from mouse and human sera that bind with rAAV-8 and rAAV-9, two vectors that are being considered for clinical trials for patients with neuromuscular disorders...
September 21, 2018: Molecular Therapy. Methods & Clinical Development
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