Featured
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Article
| Open AccessA topological refactoring design strategy yields highly stable granulopoietic proteins
Skokowa et al. reconstruct the fold of a granulopoietic cytokine, resulting in de novo, hyperstable, highly active proteins with therapeutic potential for treating several neutropenia disorders.
- Julia Skokowa
- , Birte Hernandez Alvarez
- & Mohammad ElGamacy
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Article
| Open AccessTargeting CD123 in blastic plasmacytoid dendritic cell neoplasm using allogeneic anti-CD123 CAR T cells
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and highly aggressive hematologic malignancy derived from the precursors of plasmacytoid dendritic cells. Here the authors characterize the anti-tumor activity of allogeneic anti-CD123 CAR-T cells in preclinical models of BPDCN.
- Tianyu Cai
- , Agnès Gouble
- & Marina Konopleva
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Article
| Open AccessThe engineered CD80 variant fusion therapeutic davoceticept combines checkpoint antagonism with conditional CD28 costimulation for anti-tumor immunity
CD28 costimulatory signalling can be suppressed by immune checkpoints, such as CTLA-4 and PD-1. Here the authors describe the design of the fusion therapeutic davoceticept (ALPN-202), based on a variant CD80 extracellular domain engineered to bind PD-L1 as well as CD28 and CTLA-4, providing direct T cell costimulation and dual checkpoint inhibition to enable anti-tumor immune responses.
- Mark F. Maurer
- , Katherine E. Lewis
- & Stanford L. Peng
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Article
| Open AccessMonospecific and bispecific monoclonal SARS-CoV-2 neutralizing antibodies that maintain potency against B.1.617
Despite effective vaccines against SARS-CoV-2, therapeutic options such as anti-virals and neutralizing antibodies are critical in treating disease, especially given the breakthrough infections of emerging VOCs. Here, Peng et al. generate two potent monoclonal antibodies and a bispecific antibody with two antigenrecognition variable regions targeting SARS-CoV-2 spike, provide CryoEM structures and show in vitro and in vivo efficacy of a humanized antibody against wildtype virus and delta variant.
- Lei Peng
- , Yingxia Hu
- & Sidi Chen
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Article
| Open AccessEngineered bacterial voltage-gated sodium channel platform for cardiac gene therapy
In this in vitro, in silico, and in vivo study Nguyen and colleagues show that specific and stable viral gene delivery of engineered prokaryotic voltage-gated sodium channels (BacNav) to cardiomyocytes can directly augment cardiac tissue excitability and conduction.
- Hung X. Nguyen
- , Tianyu Wu
- & Nenad Bursac
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Article
| Open AccessGenome-wide detection of CRISPR editing in vivo using GUIDE-tag
In vivo assessment of nuclease off-target activity has primarily been indirect or through ChIP-based detection of double-strand break DNA repair factors, which can be cumbersome. Here, the authors show that GUIDE-tag, enables one-step off-target genome editing analysis in mouse liver and lung.
- Shun-Qing Liang
- , Pengpeng Liu
- & Wen Xue
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Article
| Open AccessCirculating ACE2-expressing extracellular vesicles block broad strains of SARS-CoV-2
El-Shennawy et al. report that ACE2+ circulating extracellular vesicles (evACE2) are associated with COVID-19 severity and that evACE2 inhibits the infection of SARS-CoV-2 variants of concern at a higher efficacy than soluble ACE2.
- Lamiaa El-Shennawy
- , Andrew D. Hoffmann
- & Huiping Liu
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Article
| Open AccessMechanisms of SARS-CoV-2 neutralization by shark variable new antigen receptors elucidated through X-ray crystallography
Shark antibodies (Variable New Antigen Receptors, VNARs) are the smallest naturally occurring antibody fragments. Here, the authors screen a VNAR phage display library against the SARS-CoV2 receptor binding domain (RBD) and identify VNARs that neutralize the SARSCoV-2 virus and discuss their mechanisms of viral neutralization.
- Obinna C. Ubah
- , Eric W. Lake
- & Caroline J. Barelle
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Article
| Open AccessCancer immune therapy with PD-1-dependent CD137 co-stimulation provides localized tumour killing without systemic toxicity
The toxicity arising from generalised stimulation of T cells restricts applicability of CD137 agonists in cancer immune therapy. Here authors show that a bispecific antibody blocking PD-1 while activating CD137 efficiently restricts T cell activation to the tumour microenvironment, resulting in efficient tumour control and reduced liver toxicity.
- Yunqian Qiao
- , Yangmin Qiu
- & Xuan Wang
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Article
| Open AccessEngineered osteoclasts as living treatment materials for heterotopic ossification therapy
Heterotopic ossification (HO) is the formation of pathological mature bone within extraskeletal soft tissues, and there are currently no reliable methods for removing these calcified plaques. Here, the authors demonstrate that chemically engineered osteoclasts coated with tetracycline can improve their targeting capacity to ectopic calcifications, which extends their bone resorption functions for the treatment of HO.
- Wenjing Jin
- , Xianfeng Lin
- & Ruikang Tang
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Article
| Open AccessStructural insights into the clustering and activation of Tie2 receptor mediated by Tie2 agonistic antibody
Angiopoietin (Angpt)-Tie receptor 2 (Tie2) regulates vascular stability and is thus a potential therapeutic target in vascular diseases. Here, the authors report a Tie2-agonistic antibody which targets a site distinct from the Angpt 1-binding site and which influences Tie2 clustering and activation in an Angpt2 inhibition-resistant manner.
- Gyunghee Jo
- , Jeomil Bae
- & Ho Min Kim
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Article
| Open AccessCellular crosstalk regulates the aqueous humor outflow pathway and provides new targets for glaucoma therapies
Primary congenital glaucoma (PCG) is characterised by increased intraocular pressure, and variants in ANGPT1, or SVEP1 have been identified as risk alleles. Here, the authors show that deletion of these genes induces glaucoma in mice, and that activation of ANGPT1-TEK signaling ameliorates disease progression in mouse models.
- Benjamin R. Thomson
- , Pan Liu
- & Susan E. Quaggin
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Article
| Open AccessInhibiting endocytosis in CGRP+ nociceptors attenuates inflammatory pain-like behavior
The authors show the endocytotic adaptor subunit called AP2A2 is differentially expressed in CGRP+ nociceptors. Locally inhibiting nociceptor endocytosis with a lipidated AP2 inhibitor peptide reduces acute and chronic pain-like behaviour in mice and rats, indicating prolonged analgesia.
- Rasheen Powell
- , Violet A. Young
- & Arin Bhattacharjee
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Article
| Open AccessA potent SARS-CoV-2 neutralising nanobody shows therapeutic efficacy in the Syrian golden hamster model of COVID-19
Neutralizing nanobodies (Nb) are of considerable interest as therapeutic agents for COVID-19 treatment. Here, the authors functionally and structurally characterize Nbs that bind with high affinity to the receptor binding domain of the SARS-CoV-2 spike protein and show that an engineered homotrimeric Nb prevents disease progression in a Syrian hamster model of COVID-19 when administered intranasally.
- Jiandong Huo
- , Halina Mikolajek
- & Raymond J. Owens
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Article
| Open AccessExosome-mediated stable epigenetic repression of HIV-1
A strategy to control HIV-1 infection is to stably repress HIV-1 and induce “deep latency”. Here the authors show that a recombinant anti-HIV-1-1 protein can be packaged as mRNA into exosomes and delivered systemically to repress HIV-1-1 within the context of virus infected mice and achieve long term silencing of HIV-1-1 expression.
- Surya Shrivastava
- , Roslyn M. Ray
- & Kevin V. Morris
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Article
| Open AccessA cell-free nanobody engineering platform rapidly generates SARS-CoV-2 neutralizing nanobodies
Faster, higher throughput antibody engineering methods are needed. Here the authors present CeVICA, a cell-free nanobody engineering platform using ribosome display and computational clustering analysis for in vitro selection; they use this to develop nanobodies against the RBD of SARS-CoV-2 spike protein.
- Xun Chen
- , Matteo Gentili
- & Aviv Regev
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Article
| Open AccessA broadly neutralizing humanized ACE2-targeting antibody against SARS-CoV-2 variants
Here the authors report the isolation and structural and biological characterization of a humanized angiotensin-converting enzyme 2 (ACE2)-blocking antibody, which exterts potent inhibitory activity against SARS-CoV and circulating global SARS-CoV-2 lineages both in vitro and in hACE2 mouse model.
- Yanyun Du
- , Rui Shi
- & Jinghua Yan
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Article
| Open AccessElectrophysiological engineering of heart-derived cells with calcium-dependent potassium channels improves cell therapy efficacy for cardioprotection
Strategies to improve the function of damaged hearts with progenitor cells have stalled. Here, the authors show that gene transfer of a calcium-dependent potassium channel enhances the functional properties and ability of explant-derived cells to improve heart function after a heart attack.
- Patrick Vigneault
- , Sandrine Parent
- & Stanley Nattel
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Article
| Open AccessDisrupting the LINC complex by AAV mediated gene transduction prevents progression of Lamin induced cardiomyopathy
Mutations in the LaminA gene are the second most common inherited cause of Dilated Cardiomyopathy, a major form of heart failure. Here the authors show that disruption of the nuclear protein SUN1 in cardiomyocytes, by AAV mediated transduction of a SUN1 inhibitor, significantly suppress cardiomyopathy progression, providing a potential therapeutic route to treat this disease.
- Ruth Jinfen Chai
- , Hendrikje Werner
- & Colin L. Stewart
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Article
| Open AccessA human CD137×PD-L1 bispecific antibody promotes anti-tumor immunity via context-dependent T cell costimulation and checkpoint blockade
The anti-tumour effect of immune checkpoint inhibitors is potentiated by CD137 agonists in preclinical models, but translation of these results to the clinical practice is hampered by toxicity. Authors describe here a human CD137xPD-L1 bispecific antibody with improved anti-cancer activity whilst maintaining low toxicity in non-human primates.
- Cecile Geuijen
- , Paul Tacken
- & Mark Throsby
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Article
| Open AccessSelective targeting of ligand-dependent and -independent signaling by GPCR conformation-specific anti-US28 intrabodies
Various GPCRs display constitutive ligand-independent activity, but it remains unclear whether ligand-dependent and -independent conformations differ. Here the authors demonstrate the recognition and blocking of G protein recruitment of either the ligand-bound active, or the constitutively active apo-conformation of the viral GPCR US28 by different nanobodies that target similar intracellular loops of the receptor.
- Timo W. M. De Groof
- , Nick D. Bergkamp
- & Martine J. Smit
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Article
| Open AccessImproved CRISPR genome editing using small highly active and specific engineered RNA-guided nucleases
Small CRISPR Cas9 proteins have potential in gene therapies but generally have poor editing efficiency or specificity and often recognize sub-optimal PAM sequences. Here the authors characterise four small nucleases and use protein engineering to create effective in vivo editors.
- Moritz J. Schmidt
- , Ashish Gupta
- & Wayne M. Coco
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Article
| Open AccessRAS-inhibiting biologics identify and probe druggable pockets including an SII-α3 allosteric site
Oncogenic RAS mutants remain difficult to target with small molecules. Here, the authors show that RAS-binding Affimer proteins inhibit RAS signaling while binding diverse regions on the RAS surface, suggesting the potential to use Affimers as tools to identify new binding pockets and pharmacophores.
- Katarzyna Z. Haza
- , Heather L. Martin
- & Darren C. Tomlinson
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Article
| Open AccessEngineered ACE2 receptor therapy overcomes mutational escape of SARS-CoV-2
Hoshino et al., engineer a human virus receptor, hACE2, and demonstrate its potential for overcoming SARS-CoV-2 mutations that otherwise hinder therapeutic interventions. Overall, the data provide insights in to the therapeutic potential of engineered receptors.
- Yusuke Higuchi
- , Tatsuya Suzuki
- & Atsushi Hoshino
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Article
| Open AccessMultivalency transforms SARS-CoV-2 antibodies into ultrapotent neutralizers
Here, the authors combine three different antibody specificities and an Fc domain on a single multivalent molecule, resulting in high neutralization activity despite viral sequence variability.
- Edurne Rujas
- , Iga Kucharska
- & Jean-Philippe Julien
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Article
| Open AccessAntibody-drug conjugates with dual payloads for combating breast tumor heterogeneity and drug resistance
Intratumor heterogeneity in breast cancer can limit the clinical success of antibody-drug conjugates (ADCs). In this study, the authors develop dual payload Her2-ADCs that show potent anti-tumor activity against heterogeneous breast tumors in vivo.
- Chisato M. Yamazaki
- , Aiko Yamaguchi
- & Kyoji Tsuchikama
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Article
| Open AccessAntibody-based CCR5 blockade protects Macaques from mucosal SHIV transmission
CCR5 is a co-receptor for many transmitted HIV strains. Here, the authors show that biweekly injection of the CCR5-specific antibody Leronlimab protects rhesus macaques against infection following repeated intrarectal challenges of a CCR5-tropic SHIV.
- Xiao L. Chang
- , Gabriela M. Webb
- & Jonah B. Sacha
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Article
| Open AccessDevelopment of selective bispecific Wnt mimetics for bone loss and repair
Antibody-based Wnt agonists are able to phenocopy Wnt signaling in vivo resulting in increased bone density, repair, and strength. Here, the authors show that Wnt agonists can reverse bone loss associated with ovariectomy and build stronger bone when administered after fracture.
- Tristan W. Fowler
- , Troy L. Mitchell
- & Yang Li
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Article
| Open AccessA human antibody selective for transthyretin amyloid removes cardiac amyloid through phagocytic immune cells
Analyzing memory B cell repertoires of the healthy elderly enabled Michalon et al. to develop a recombinant human antibody selective for transthyretin amyloid. This antibody removes cardiac amyloid through recruitment of phagocytic immune cells.
- Aubin Michalon
- , Andreas Hagenbuch
- & Jan Grimm
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Article
| Open AccessA SARS-CoV-2 neutralizing antibody with extensive Spike binding coverage and modified for optimal therapeutic outcomes
Antibodies against SARS-CoV-2 S protein can provide a treatment strategy for COVID-19. Here, Guo et al. provide the crystal structure of a SARS-CoV2 neutralizing antibody isolated from a convalescent patient and highlight the therapeutic efficacy in a rhesus monkey model of an engineered version with optimized pharmacokinetic and safety profile.
- Yu Guo
- , Lisu Huang
- & Zihe Rao
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Article
| Open AccessSARS-CoV-2 neutralizing human recombinant antibodies selected from pre-pandemic healthy donors binding at RBD-ACE2 interface
Antibodies targeting the spike protein of coronaviruses are potential candidates for therapeutic development. Here, Bertoglio et al. use phage display to select anti-SARS-CoV-2 spike antibodies from the human naïve universal antibody gene libraries HAL9/10 that block interaction with ACE2 receptor to inhibit infection.
- Federico Bertoglio
- , Doris Meier
- & Michael Hust
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Article
| Open AccessLasso-grafting of macrocyclic peptide pharmacophores yields multi-functional proteins
RaPID (Random non-standard Peptides Integrated Discovery) enables discovery of small macrocyclic peptides binding desired targets. Here, the authors propose lasso-grafting: the RaPID-derived peptides are implanted onto diverse proteins and maintain both the binding properties of the cyclic peptide and the host protein function.
- Emiko Mihara
- , Satoshi Watanabe
- & Junichi Takagi
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Article
| Open AccessShort antisense oligonucleotides alleviate the pleiotropic toxicity of RNA harboring expanded CGG repeats
Fragile X-associated tremor/ataxia syndrome is a neurodegenerative disease caused by toxic RNA containing expanded CGG repeats. Here, the authors show that synthetic oligonucleotides targeting the RNA repeats decrease the pleiotropic effect of this toxic molecule in cellular and animal models of the disease.
- Magdalena Derbis
- , Emre Kul
- & Krzysztof Sobczak
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Article
| Open AccessDirect control of CAR T cells through small molecule-regulated antibodies
Many next-generation antibody therapeutics have enhanced potency but the risk of adverse events. Here the authors develop a conditionally activated, single-module CAR.
- Spencer Park
- , Edward Pascua
- & Javier Chaparro-Riggers
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Article
| Open AccessDutaFabs are engineered therapeutic Fab fragments that can bind two targets simultaneously
Bispecific antibodies can bind to two distinct targets though the fusion of two different Fv regions. In this study, the authors develop DutaFabs that present two separated and independent antigen binding sites within the same Fv region, giving rise to bispecific Fab fragments.
- Roland Beckmann
- , Kristian Jensen
- & Hubert Kettenberger
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Article
| Open AccessA therapeutic neutralizing antibody targeting receptor binding domain of SARS-CoV-2 spike protein
Therapies and vaccines for COVID-19, caused by the SARS-CoV-2 viral pandemic, are urgently needed. Here the authors establish and screen an antibody library from a convalescent COVID-19 patient to isolate a neutralizing antibody with the ability to reduce viral titer and alleviate symptoms in ferret, hamster, and rhesus monkey infection models.
- Cheolmin Kim
- , Dong-Kyun Ryu
- & Soo-Young Lee
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Comment
| Open AccessTurning genes into medicines—what have we learned from gene therapy drug development in the past decade?
Gene and cell therapy products approved over the past decade in Europe and North America have provided new therapeutic options for single gene disorders and for hematologic malignancies. Lessons learned, and limitations identified, are reviewed.
- Katherine A. High
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Article
| Open AccessStructure of Epstein-Barr virus tegument protein complex BBRF2-BSRF1 reveals its potential role in viral envelopment
Epstein-Barr virus (EBV) tegument proteins BBRF2 and BSRF1 have been suggested to form a hetero-complex. Here, He et al. provide the crystal structures of BBRF2 alone and in complex with BSRF1 and suggest that the complex tethers EBV nucleocapsids to the Golgi membrane, facilitating secondary envelopment.
- Hui-Ping He
- , Meng Luo
- & Song Gao
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Article
| Open AccessFormat chain exchange (FORCE) for high-throughput generation of bispecific antibodies in combinatorial binder-format matrices
Bispecific antibodies have been generated in many different formats and it is becoming clear that rational design alone cannot create optimal functionalities. Here the authors introduce the high throughput methodology, Format Chain Exchange (FORCE), to enable combinatorial generation of bispecific antibodies.
- Stefan Dengl
- , Klaus Mayer
- & Ulrich Brinkmann
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Article
| Open AccessHumanized single domain antibodies neutralize SARS-CoV-2 by targeting the spike receptor binding domain
Here, using a humanized phage display library with recombinant SARS- CoV-2 receptor binding domain (RBD) proteins, the authors identify a number of single domain antibodies (sdAbs) that neutralize SARS-CoV-2 in vitro by inhibiting the interaction of the RDB with the host entry receptor ACE2.
- Xiaojing Chi
- , Xiuying Liu
- & Wei Yang
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Article
| Open AccessOsteoclast-associated receptor blockade prevents articular cartilage destruction via chondrocyte apoptosis regulation
Osteoarthritis (OA) is associated with cartilage disruption, but the underlying mechanisms remain unclear. Here, the authors show that expression of osteoclast-associated receptor (OSCAR) is associated with OA, that its genetic ablation or targeting with OSCAR-Fc fusion protein ameliorates OA in mice by decreasing chondrocyte apoptosis.
- Doo Ri Park
- , Jihee Kim
- & Soo Young Lee
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Article
| Open AccessA cross-reactive human IgA monoclonal antibody blocks SARS-CoV-2 spike-ACE2 interaction
Here, Ejemel et al. report the identification and characterization of a cross-neutralizing human IgA monoclonal antibody, named MAb362, that binds the receptor-binding domain of SARS-CoV-2 Spike, blocking its interaction with the ACE2 host receptor.
- Monir Ejemel
- , Qi Li
- & Yang Wang
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Article
| Open AccessSelective inhibition of STAT3 signaling using monobodies targeting the coiled-coil and N-terminal domains
STAT3 is an attractive therapeutic target but its homology with other STAT proteins complicates the development of selective inhibitors. Here, the authors develop monobodies with high affinity and selectivity for STAT3 and show that they can interfere with cellular STAT3 activity.
- Grégory La Sala
- , Camille Michiels
- & Oliver Hantschel
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Article
| Open AccessCyclic peptide FXII inhibitor provides safe anticoagulation in a thrombosis model and in artificial lungs
Inhibiting thrombosis without inducing bleeding is a major challenge for anticoagulant agents. Here the authors describe a synthetic FXIIa inhibitor able to efficiently prevent thrombosis in mice and suppress coagulation in artificial lungs in rabbits without increasing the risk of bleeding.
- Jonas Wilbs
- , Xu-Dong Kong
- & Christian Heinis
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Article
| Open AccessSilencing hepatic MCJ attenuates non-alcoholic fatty liver disease (NAFLD) by increasing mitochondrial fatty acid oxidation
Non-alcoholic fatty liver (NAFLD) disease causes degeneration of the liver, affects about 25% of people globally, and has no approved treatment. Here, the authors show that the therapeutic siRNA-driven silencing of MCJ in the liver is an effective and safe treatment for NAFLD in multiple mouse models.
- Lucía Barbier-Torres
- , Karen A. Fortner
- & Mercedes Rincón
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Article
| Open AccessStructural characterization of a novel human adeno-associated virus capsid with neurotropic properties
Adeno-associated viruses (AAVs) are vehicles for gene therapy in humans, but currently only a limited amount of AAV serotypes is available. Here, the authors identify a novel AAV, AAVv66, and demonstrate enhanced production yields, virion stability, and CNS transduction compared to the clinically approved serotype AAV2.
- Hung-Lun Hsu
- , Alexander Brown
- & Guangping Gao
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Article
| Open AccessTargeted inhibition of activated protein C by a non-active-site inhibitory antibody to treat hemophilia
Activated protein C (APC) is a plasma serine protease with antithrombotic and cytoprotective functions. Here, the authors develop a monoclonal antibody that specifically inhibits APC’s anticoagulant function without compromising its cytoprotective function, and shows efficacy in animal models.
- Xiao-Yan Zhao
- , Andreas Wilmen
- & Volker Laux
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Article
| Open AccessReverse engineering synthetic antiviral amyloids
Some human amyloid proteins have been shown to interact with viral proteins, suggesting that they may have potential as therapeutic agents. Here the authors design synthetic amyloids specific for influenza A and Zika virus proteins, respectively, and show that they can inhibit viral replication.
- Emiel Michiels
- , Kenny Roose
- & Joost Schymkowitz
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Article
| Open AccessNeutralization of SARS-CoV-2 spike pseudotyped virus by recombinant ACE2-Ig
SARS-CoV-2 uses ACE2 as the entry receptor. Here, the authors show that an ACE2-Ig fusion protein inhibits entry of virus pseudotyped with the SARS-CoV-2 spike protein, show differential binding kinetics of SARS-CoV and SARSCoV-2 spike proteins to ACE2, and determine pharmakocinetic parameters of ACE2-Ig in mice.
- Changhai Lei
- , Kewen Qian
- & Shi Hu
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