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Engineering Yarrowia lipolytica for Production of Fatty Alcohols with YaliBrick Vectors.

Methods Mol Biol 2021 ;2307:159-173

Department of Chemical, Biochemical and Environmental Engineering, University of Maryland Baltimore County, Baltimore, MD, USA.

Biosynthesis of fatty alcohol holds great promise as substitute to replace petroleum-derived fatty alcohols to mitigate environmental concerns and reduce earth's carbon footprint. In this protocol, we detail the procedures of how to use the YaliBrick gene assembly platform to achieve modular assembly of fatty alcohol pathway in Y. lipolytica. Read More

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January 2021

Best of most possible worlds: Hybrid gene therapy vectors based on parvoviruses and heterologous viruses.

Mol Ther 2021 Apr 5. Epub 2021 Apr 5.

Department of Infectious Diseases/Virology, Medical Faculty, University of Heidelberg, Heidelberg, Germany; BioQuant, University of Heidelberg, Germany; German Center for Infection Research (DZIF) and German Center for Cardiovascular Research (DZHK), partner site Heidelberg, Germany. Electronic address:

Parvoviruses and especially the Adeno-associated virus (AAV) species provide an exciting and versatile platform for the rational design or molecular evolution of human gene therapy vectors, documented by literature from over half a century, hundreds of clinical trials and the recent commercialization of multiple AAV gene therapeutics. For the last three decades, the power of these vectors has been further potentiated through various types of hybrid vectors created by intra- or inter-genus juxtaposition of viral DNA and protein cis elements, or by synergistic complementation of parvoviral features with those of heterologous, prokaryotic or eukaryotic viruses. Here, we provide an overview of the history and promise of this rapidly expanding field of hybrid parvoviral gene therapy vectors, starting with early generations of chimeric particles composed of a recombinant AAV genome encapsidated in shells of synthetic AAVs, or of adeno-, herpes-, baculo- or protoparvoviruses. Read More

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Immunogenicity of Varicella-Zoster Virus Glycoprotein E Formulated with Lipid Nanoparticles and Nucleic Immunostimulators in Mice.

Vaccines (Basel) 2021 Mar 25;9(4). Epub 2021 Mar 25.

Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming 650118, China.

Theoretically, the subunit herpes zoster vaccine Shingrix could be used as a varicella vaccine that avoids the risk of developing shingles from vaccination, but bedside mixing strategies and the limited supply of the adjuvant component QS21 have made its application economically impracticable. With lipid nanoparticles (LNPs) that were approved by the FDA as vectors for severe acute respiratory syndrome coronavirus 2 vaccines, we designed a series of vaccines efficiently encapsulated with varicella-zoster virus glycoprotein E (VZV-gE) and nucleic acids including polyinosinic-polycytidylic acid (Poly I:C) and the natural phosphodiester CpG oligodeoxynucleotide (CpG ODN), which was approved by the FDA as an immunostimulator in a hepatitis B vaccine. Preclinical trial in mice showed that these LNP vaccines could induce VZV-gE IgG titers more than 16 times those induced by an alum adjuvant, and immunized serum could block in vitro infection completely at a dilution of 1:80, which indicated potential as a varicella vaccine. Read More

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Lantana camara L. essential oils from Vietnam: Chemical composition, molluscicidal, and mosquito larvicidal activity.

Chem Biodivers 2021 Mar 29. Epub 2021 Mar 29.

Univesity of Alabama in Huntsville, Department of Chemistry, 301 Sparkman Drive, Not Available, 35899, Huntsville, UNITED STATES.

Lantana camara is a troublesome invasive plant introduced to many tropical regions, including Southeast Asia.  However, the plant does hold promise as a source of essential oils that may be explored for potential use.  Fresh water snails such as Pomacea canaliculata , Gyraulus convexiusculus , and Tarebia granifera can be problematic agricultural pests as well as hosts for parasitic worms. Read More

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Haemophilia, state of the art and new therapeutic opportunities, a regulatory perspective.

Br J Clin Pharmacol 2021 Mar 27. Epub 2021 Mar 27.

National Center for Drug Research and Evaluation, Istituto Superiore di Sanità, Rome, Italy.

Haemophilia A and B are rare bleeding disorders. Over the past decades, they have been transformed from debilitating diseases to manageable conditions in the Western world. However, optimizing haemophilia care remains challenging in developing countries. Read More

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Multiplexing viral approaches to the study of the neuronal circuits.

J Neurosci Methods 2021 Mar 20;357:109142. Epub 2021 Mar 20.

Kavli Institute for Systems Neuroscience and Centre for Neural Computation, NTNU, Trondheim, Norway. Electronic address:

Neural circuits are composed of multitudes of elaborately interconnected cell types. Understanding neural circuit function requires not only cell-specific knowledge of connectivity, but the ability to record and manipulate distinct cell types independently. Recent advances in viral vectors promise the requisite specificity to perform true "circuit-breaking" experiments. Read More

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Adenovirus-vectored T cell vaccine for hepacivirus shows reduced effectiveness against a CD8 T cell escape variant in rats.

PLoS Pathog 2021 Mar 18;17(3):e1009391. Epub 2021 Mar 18.

Center for Vaccines and Immunity, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States of America.

There is an urgent need for a vaccine to prevent chronic infection by hepatitis C virus (HCV) and its many genetic variants. The first human vaccine trial, using recombinant viral vectors that stimulate pan-genotypic T cell responses against HCV non-structural proteins, failed to demonstrate efficacy despite significant preclinical promise. Understanding the factors that govern HCV T cell vaccine success is necessary for design of improved immunization strategies. Read More

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Gene engineered mesenchymal stem cells: greater transgene expression and efficacy with minicircle vs. plasmid DNA vectors in a mouse model of acute lung injury.

Stem Cell Res Ther 2021 Mar 16;12(1):184. Epub 2021 Mar 16.

Ottawa Hospital Research Institute, Ottawa, ON, Canada.

Background: Acute lung injury (ALI) and in its severe form, acute respiratory distress syndrome (ARDS), results in increased pulmonary vascular inflammation and permeability and is a major cause of mortality in many critically ill patients. Although cell-based therapies have shown promise in experimental ALI, strategies are needed to enhance the potency of mesenchymal stem cells (MSCs) to develop more effective treatments. Genetic modification of MSCs has been demonstrated to significantly improve the therapeutic benefits of these cells; however, the optimal vector for gene transfer is not clear. Read More

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Clinical development of retroviral replicating vector Toca 511 for gene therapy of cancer.

Expert Opin Biol Ther 2021 Mar 16. Epub 2021 Mar 16.

Tocagen, Inc., San Diego, California, U.S.A.

Introduction: The use of tumor-selectively replicating viruses is a rapidly expanding field that is showing considerable promise for cancer treatment. Retroviral replicating vectors (RRV) are unique among the various replication-competent viruses currently being investigated for potential clinical utility, because they permanently integrate into the cancer cell genome, and are capable of long-term persistence within tumors. RRV can mediate efficient tumor-specific delivery of prodrug activator genes, and subsequent prodrug treatment leads to synchronized cell killing of infected cancer cells, as well as activation of anti-tumor immune responses. Read More

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Leber congenital amaurosis/early-onset severe retinal dystrophy: current management and clinical trials.

Br J Ophthalmol 2021 Mar 12. Epub 2021 Mar 12.

UCL Institute of Ophthalmology, University College London, London, UK

Leber congenital amaurosis (LCA) is a severe congenital/early-onset retinal dystrophy. Given its monogenic nature and the immunological and anatomical privileges of the eye, LCA has been particularly targeted by cutting-edge research. In this review, we describe the current management of LCA, and highlight the clinical trials that are on-going and planned. Read More

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MOLECULAR MEDICINE: Found in Translation.

Authors:
Stuart H Orkin

Med (N Y) 2021 Feb 12;2(2):122-136. Epub 2021 Jan 12.

Dana Farber/Boston Children's Cancer & Blood Disorders Center, Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115.

Studies of the major hemoglobin disorders, β-thalassemia and sickle cell disease (SCD), have laid a foundation for molecular medicine. While enormous progress has been made in understanding gene structure and regulation, translating molecular insights to therapy for the many individuals affected with these disorders has been challenging. Advances in three activities have recently converged to bring novel genetic and potentially curative treatments to clinical trials. Read More

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February 2021

The Landscape of Non-Viral Gene Augmentation Strategies for Inherited Retinal Diseases.

Int J Mol Sci 2021 Feb 26;22(5). Epub 2021 Feb 26.

UCL Institute of Ophthalmology, London EC1V 9EL, UK.

Inherited retinal diseases (IRDs) are a heterogeneous group of disorders causing progressive loss of vision, affecting approximately one in 1000 people worldwide. Gene augmentation therapy, which typically involves using adeno-associated viral vectors for delivery of healthy gene copies to affected tissues, has shown great promise as a strategy for the treatment of IRDs. However, the use of viruses is associated with several limitations, including harmful immune responses, genome integration, and limited gene carrying capacity. Read More

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February 2021

The Eagle effect in the Wolbachia-worm symbiosis.

Parasit Vectors 2021 Feb 24;14(1):118. Epub 2021 Feb 24.

Department of Pharmaceutical Chemistry, University of California, San Francisco, CA, USA.

Background: Onchocerciasis (river blindness) and lymphatic filariasis (elephantiasis) are two human neglected tropical diseases that cause major disabilities. Mass administration of drugs targeting the microfilarial stage has reduced transmission and eliminated these diseases in several countries but a macrofilaricidal drug that kills or sterilizes the adult worms is critically needed to eradicate the diseases. The causative agents of onchocerciasis and lymphatic filariasis are filarial worms that harbor the endosymbiotic bacterium Wolbachia. Read More

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February 2021

International, Transdisciplinary, and Ecohealth Action for Sustainable Agriculture in Asia.

Front Public Health 2021 5;9:592311. Epub 2021 Feb 5.

Animal and Human Health Program, International Livestock Research Institute, Nairobi, Kenya.

Sustainably intensifying agriculture to secure food for people, while minimizing the human, animal, and environmental health impacts is an unprecedented global food security challenge. Action research is needed to understand and mitigate impacts, with Ecosystem approaches to health (Ecohealth) emerging as a promising framework to support such efforts. Yet, few have critically examined the application of Ecohealth principles in an agricultural context, particularly in Southeast Asia where agricultural intensification is rapidly expanding. Read More

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February 2021

Layer-by-Layer technique as a versatile tool for gene delivery applications.

Expert Opin Drug Deliv 2021 Feb 18:1-19. Epub 2021 Feb 18.

Laboratory of Micro-Encapsulation and Targeted Delivery of Biologically Active Compounds, Peter The Great St. Petersburg Polytechnic University , St. Petersburg, Russia.

: Gene therapy is a breakthrough medical field which focuses on the therapeutic delivery of recombinant nucleic acids in order to treat or prevent a broad spectrum of diseases. However, a number of important obstacles remain before its wide introduction into clinical practice can be envisaged. One of the biggest bottlenecks is the lack of efficient and safe delivery technologies, particularly, for distribution. Read More

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February 2021

Enhancement of Therapies for Glioblastoma (GBM) Using Nanoparticle-based Delivery Systems.

AAPS PharmSciTech 2021 Feb 11;22(2):71. Epub 2021 Feb 11.

Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa, Iowa City, Iowa, 52242, USA.

Glioblastoma multiforme (GBM) is the most aggressive type of malignant brain tumor. Current FDA-approved treatments include surgical resection, radiation, and chemotherapy, while hyperthermia, immunotherapy, and most relevantly, nanoparticle (NP)-mediated delivery systems or combinations thereof have shown promise in preclinical studies. Drug-carrying NPs are a promising approach to brain delivery as a result of their potential to facilitate the crossing of the blood-brain barrier (BBB) via two main types of transcytosis mechanisms: adsorptive-mediated transcytosis (AMT) and receptor-mediated transcytosis (RMT). Read More

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February 2021

Visceral adipose tissue-directed FGF21 gene therapy improves metabolic and immune health in BTBR mice.

Mol Ther Methods Clin Dev 2021 Mar 25;20:409-422. Epub 2020 Dec 25.

Department of Cancer Biology & Genetics, College of Medicine, The Ohio State University, Columbus, OH 43210, USA.

Fibroblast growth factor 21 (FGF21) is a peptide hormone that serves as a potent effector of energy homeostasis. Increasingly, FGF21 is viewed as a promising therapeutic agent for type 2 diabetes, fatty liver disease, and other metabolic complications. Exogenous administration of native FGF21 peptide has proved difficult due to unfavorable pharmacokinetic properties. Read More

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Gene delivery to the hypoglossal motor system: preclinical studies and translational potential.

Gene Ther 2021 Feb 11. Epub 2021 Feb 11.

Department of Physical Therapy, University of Florida, Gainesville, FL, USA.

Dysfunction and/or reduced activity in the tongue muscles contributes to conditions such as dysphagia, dysarthria, and sleep disordered breathing. Current treatments are often inadequate, and the tongue is a readily accessible target for therapeutic gene delivery. In this regard, gene therapy specifically targeting the tongue motor system offers two general strategies for treating lingual disorders. Read More

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February 2021

A Code of Ethics for Gene Drive Research.

CRISPR J 2021 Feb 10;4(1):19-24. Epub 2021 Feb 10.

Molecular Pathology Unit, Massachusetts General Hospital, Charlestown, Massachusetts, USA.

Gene drives hold promise for use in controlling insect vectors of diseases, agricultural pests, and for conservation of ecosystems against invasive species. At the same time, this technology comes with potential risks that include unknown downstream effects on entire ecosystems as well as the accidental or nefarious spread of organisms that carry the gene drive machinery. A code of ethics can be a useful tool for all parties involved in the development and regulation of gene drives and can be used to help ensure that a balanced analysis of risks, benefits, and values is taken into consideration in the interest of society and humanity. Read More

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February 2021

Viral-Vector-Delivered Anti-Angiogenic Therapies to the Eye.

Pharmaceutics 2021 Feb 5;13(2). Epub 2021 Feb 5.

A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, P.O. Box 1627, 70211 Kuopio, Finland.

Pathological vessel growth harms vision and may finally lead to vision loss. Anti-angiogenic gene therapy with viral vectors for ocular neovascularization has shown great promise in preclinical studies. Most of the studies have been conducted with different adeno-associated serotype vectors. Read More

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February 2021

Engineering of human induced pluripotent stem cells via human artificial chromosome vectors for cell therapy and disease modeling.

Mol Ther Nucleic Acids 2021 Mar 19;23:629-639. Epub 2020 Dec 19.

Laboratory of Bioengineering, Tokyo University of Pharmacy and Life Sciences, 1432-1, Horinouchi, Hachioji, Tokyo 192-0392, Japan.

Genetic engineering of induced pluripotent stem cells (iPSCs) holds great promise for gene and cell therapy as well as drug discovery. However, there are potential concerns regarding the safety and control of gene expression using conventional vectors such as viruses and plasmids. Although human artificial chromosome (HAC) vectors have several advantages as a gene delivery vector, including stable episomal maintenance and the ability to carry large gene inserts, the full potential of HAC transfer into iPSCs still needs to be explored. Read More

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Surgical approach to the facial recess influences the acceptable trajectory of cochlear implantation electrodes.

Eur Arch Otorhinolaryngol 2021 Feb 5. Epub 2021 Feb 5.

Department of Surgery (Otolaryngology), University of Melbourne, Level 5, Royal Victorian Eye and Ear Hospital, 32, Gisborne Street, East Melbourne, VIC, 3002, Australia.

Purpose: To provide practical guidance to the operative surgeon by mapping the location, where acceptable straight-line virtual cochlear implant electrode trajectories intersect the facial recess. In addition, to investigate the influence of facial recess preparation, virtual electrode width and surgical approach to the cochlea on these available trajectories.

Methods: The study was performed on imaging data from eight cadaveric temporal bones within the University of Melbourne Virtual Reality (VR) Temporal Bone Surgery Simulator. Read More

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February 2021

Structures of active-state orexin receptor 2 rationalize peptide and small-molecule agonist recognition and receptor activation.

Nat Commun 2021 02 5;12(1):815. Epub 2021 Feb 5.

Computational & Structural Chemistry, MRL, Merck & Co., Inc, West Point, PA, USA.

Narcolepsy type 1 (NT1) is a chronic neurological disorder that impairs the brain's ability to control sleep-wake cycles. Current therapies are limited to the management of symptoms with modest effectiveness and substantial adverse effects. Agonists of the orexin receptor 2 (OXR) have shown promise as novel therapeutics that directly target the pathophysiology of the disease. Read More

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February 2021

Gene-based therapies for neurodegenerative diseases.

Nat Neurosci 2021 03 1;24(3):297-311. Epub 2021 Feb 1.

Department of Pathology, University of California, San Diego, La Jolla, CA, USA.

Gene therapy is making a comeback. With its twin promise of targeting disease etiology and 'long-term correction', gene-based therapies (defined here as all forms of genome manipulation) are particularly appealing for neurodegenerative diseases, for which conventional pharmacologic approaches have been largely disappointing. The recent success of a viral-vector-based gene therapy in spinal muscular atrophy-promoting survival and motor function with a single intravenous injection-offers a paradigm for such therapeutic intervention and a platform to build on. Read More

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Using viral vectors to deliver local immunotherapy to glioblastoma.

Neurosurg Focus 2021 02;50(2):E4

The treatment for glioblastoma (GBM) has not seen significant improvement in over a decade. Immunotherapies target the immune system against tumor cells and have seen success in various cancer types. However, the efficacy of immunotherapies in GBM thus far has been limited. Read More

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February 2021

Insights into the Role of Tick Salivary Protease Inhibitors during Ectoparasite-Host Crosstalk.

Int J Mol Sci 2021 Jan 17;22(2). Epub 2021 Jan 17.

Laboratory of Genomics and Proteomics of Disease Vectors, Biology Centre CAS, Institute of Parasitology, Branišovská 1160/31, 37005 České Budějovice, Czech Republic.

Protease inhibitors (PIs) are ubiquitous regulatory proteins present in all kingdoms. They play crucial tasks in controlling biological processes directed by proteases which, if not tightly regulated, can damage the host organism. PIs can be classified according to their targeted proteases or their mechanism of action. Read More

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January 2021

Brain penetrating peptides and peptide-drug conjugates to overcome the blood-brain barrier and target CNS diseases.

Wiley Interdiscip Rev Nanomed Nanobiotechnol 2021 Jan 20:e1695. Epub 2021 Jan 20.

Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, Texas, USA.

Nearly one in six people worldwide suffer from disorders of the central nervous system (CNS). There is an urgent need for effective strategies to improve the success rates in CNS drug discovery and development. The lack of effective technologies for delivering drugs and genes to the brain due to the blood-brain barrier (BBB), a structural barrier that effectively blocks most neurotherapeutic agents from reaching the brain, has posed a formidable hurdle for CNS drug development. Read More

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January 2021

PDGF-BB and IL-4 co-overexpression is a potential strategy to enhance mesenchymal stem cell-based bone regeneration.

Stem Cell Res Ther 2021 Jan 7;12(1):40. Epub 2021 Jan 7.

Department of Orthopaedic Surgery, Stanford University, Stanford, CA, USA.

Background: Mesenchymal stem cell (MSC)-based therapy has the potential for immunomodulation and enhancement of tissue regeneration. Genetically modified MSCs that over-express specific cytokines, growth factors, or chemokines have shown great promise in pre-clinical studies. In this regard, the anti-inflammatory cytokine interleukin (IL)-4 converts pro-inflammatory M1 macrophages into an anti-inflammatory M2 phenotype; M2 macrophages mitigate chronic inflammation and enhance osteogenesis by MSC lineage cells. Read More

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January 2021

Mesenchymal Stem Cells as Therapeutic Agents and Novel Carriers for the Delivery of Candidate Genes in Acute Kidney Injury.

Stem Cells Int 2020 11;2020:8875554. Epub 2020 Dec 11.

First Hospital of Shanxi Medical University, No. 85, Jiefangnan Road, Taiyuan, 030001 Shanxi, China.

Acute kidney injury (AKI) is a heterogeneous syndrome characterized by a dramatic increase in serum creatinine. Mild AKI may merely be confined to kidney damage and resolve within days; however, severe AKI commonly involves extrarenal organ dysfunction and is associated with high mortality. There is no specific pharmaceutical treatment currently available that can reverse the course of this disease. Read More

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December 2020