scholarly journals 2219

2017 ◽  
Vol 1 (S1) ◽  
pp. 59-59
Author(s):  
Shaheen Kurani ◽  
Nicolas Madigan ◽  
Karl Clark ◽  
Stephen Ekker ◽  
Nathan Staff ◽  
...  
Keyword(s):  
Cell Survival ◽  
Targeted Delivery ◽  
Transfection Efficiency ◽  
Current Treatment ◽  
Safe Harbor ◽  
Systemic Delivery ◽  
Transcription Activator ◽  
Field Methods ◽  
A Cell ◽  
The Central Nervous System

OBJECTIVES/SPECIFIC AIMS: The current treatment for amyotrophic lateral sclerosis (ALS) includes systemic delivery of neurotrophic factors (NTFs). Although this approach may seem theoretically sound, NTF efficacy within the central nervous system (CNS) is largely limited by the blood-brain barrier. Thus, a cell-based approach, which allows for targeted delivery of molecular therapies locally from the CNS, could lead to a paradigm shift in the field. METHODS/STUDY POPULATION: The Windebank and Staff group at Mayo Clinic completed a Phase I dose-escalation safety trial of autologous, adipose-derived mesenchymal stem cells (adMSCs) in an effort to move toward personalized medical treatment of ALS. The adMSCs were injected into the intrathecal space by lumbar puncture in 27 patients and the results showed an excellent safety profile across a range of doses. The team is moving forward with this idea by using gene-editing technology to develop clinical-grade, genetically modified autologous MSCs. The patient-derived adMSCs are modified at defined “safe-harbor” regions of the human genome through transcription activator-like effector nuclease (TALEN) technology. RESULTS/ANTICIPATED RESULTS: Our results show that electroporating adMSCs with plasmid DNA leads to efficient GFP or TALEN transgene expression, but yields low cell survival and a low rate of genetic modification. DISCUSSION/SIGNIFICANCE OF IMPACT: It can be concluded that: (1) TALEN technology may be used to target safe harbor loci for gene integration to produce therapeutic adMSC for ALS. (2) Primary barriers to adMSC modification are inefficient TALEN and donor template uptake, low cutting efficiency, and poor cell survival after electroporation. Future directions include optimizing the protocol to obtain 48 base pairs in the homology arms and increasing transfection efficiency.

scholarly journals Promising Nanotechnology Approaches in Treatment of Autoimmune Diseases of Central Nervous System

2020 ◽  
Vol 10 (6) ◽  
pp. 338 ◽  
Author(s):  
Maria Chountoulesi ◽  
Costas Demetzos
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Targeted Delivery ◽  
Current Treatment ◽  
Autoimmune Encephalomyelitis ◽  
Axon Damage ◽  
The Central Nervous System ◽  
Therapeutic Tools ◽  
High Bioavailability ◽  
Experimental Autoimmune

Multiple sclerosis (MS) is a chronic, autoimmune, neurodegenerative disease of the central nervous system (CNS) that yields to neuronal axon damage, demyelization, and paralysis. Although several drugs were designed for the treatment of MS, with some of them being approved in the last few decades, the complete remission and the treatment of progressive forms still remain a matter of debate and a medical challenge. Nanotechnology provides a variety of promising therapeutic tools that can be applied for the treatment of MS, overcoming the barriers and the limitations of the already existing immunosuppressive and biological therapies. In the present review, we explore literature case studies on the development of drug delivery nanosystems for the targeted delivery of MS drugs in the pathological tissues of the CNS, providing high bioavailability and enhanced therapeutic efficiency, as well as nanosystems for the delivery of agents to facilitate efficient remyelination. Moreover, we present examples of tolerance-inducing nanocarriers, being used as promising vaccines for antigen-specific immunotherapy of MS. We emphasize on liposomes, as well as lipid- and polymer-based nanoparticles. Finally, we highlight the future perspectives given by the nanotechnology field toward the improvement of the current treatment of MS and its animal model, experimental autoimmune encephalomyelitis (EAE).

Presence of antibody in virus-infected brain cells of SSPE ferrets

1983 ◽  
Vol 41 ◽  
pp. 804-805
Author(s):  
Hannah R. Brown ◽  
Tammy L. Donato ◽  
Halldor Thormar
Keyword(s):  
Measles Virus ◽  
Plasma Cells ◽  
Subacute Sclerosing Panencephalitis ◽  
Protein A ◽  
Neutralizing Antibody ◽  
Brain Cells ◽  
Antibody Titers ◽  
A Cell ◽  
The Central Nervous System ◽  
The Brain

Measles virus specific immunoglobulin G (IgG) has been found in the brains of patients with subacute sclerosing panencephalitis (SSPE), a slowly progressing disease of the central nervous system (CNS) in children. IgG/albumin ratios indicate that the antibodies are synthesized within the CNS. Using the ferret as an animal model to study the disease, we have been attempting to localize the Ig's in the brains of animals inoculated with a cell associated strain of SSPE. In an earlier report, preliminary results using Protein A conjugated to horseradish peroxidase (PrAPx) (Dynatech Diagnostics Inc., South Windham, ME.) to detect antibodies revealed the presence of immunoglobulin mainly in antibody-producing plasma cells in inflammatory lesions and not in infected brain cells.In the present experiment we studied the brain of an SSPE ferret with neutralizing antibody titers of 1:1024 in serum and 1:512 in CSF at time of sacrifice 7 months after i.c. inoculation with SSPE measles virus-infected cells. The animal was perfused with saline and portions of the brain and spinal cord were immersed in periodate-lysine-paraformaldehyde (P-L-P) fixative. The ferret was not perfused with fixative because parts of the brain were used for virus isolation.

Stepwise Development of Biomimetic Chimeric Peptides for Gene Delivery

2020 ◽  
Vol 27 (8) ◽  
pp. 698-710
Author(s):  
Roya Cheraghi ◽  
Mahboobeh Nazari ◽  
Mohsen Alipour ◽  
Saman Hosseinkhani
Keyword(s):  
Gene Delivery ◽  
Targeted Delivery ◽  
Viral Vectors ◽  
Large Scale ◽  
Transfection Efficiency ◽  
Cationic Lipids ◽  
Target Cells ◽  
Scale Production ◽  
Stepwise Development ◽  
Chimeric Peptides

Gene-based therapy largely relies on the vector type that allows a selective and efficient transfection into the target cells with maximum efficacy and minimal toxicity. Although, genes delivered utilizing modified viruses transfect efficiently and precisely, these vectors can cause severe immunological responses and are potentially carcinogenic. A promising method of overcoming this limitation is the use of non-viral vectors, including cationic lipids, polymers, dendrimers, and peptides, which offer potential routes for compacting DNA for targeted delivery. Although non-viral vectors exhibit reduced transfection efficiency compared to their viral counterpart, their superior biocompatibility, non-immunogenicity and potential for large-scale production make them increasingly attractive for modern therapy. There has been a great deal of interest in the development of biomimetic chimeric peptides. Biomimetic chimeric peptides contain different motifs for gene translocation into the nucleus of the desired cells. They have motifs for gene targeting into the desired cell, condense DNA into nanosize particles, translocate the gene into the nucleus and enhance the release of the particle into the cytoplasm. These carriers were developed in recent years. This review highlights the stepwise development of the biomimetic chimeric peptides currently being used in gene delivery.

scholarly journals Improving the Utility of a Dynorphin Peptide Analogue Using Mannosylated Glycoliposomes

2021 ◽  
Vol 22 (15) ◽  
pp. 7996
Author(s):  
Jordan D. Lewicky ◽  
Nya L. Fraleigh ◽  
Alexandrine L. Martel ◽  
Thi M.-D. Nguyen ◽  
Peter W. Schiller ◽  
...  
Keyword(s):  
Targeted Delivery ◽  
Delivery Systems ◽  
Kappa Opioid Receptor ◽  
Antagonist Activity ◽  
Peptide Analogue ◽  
Nanoparticle Delivery ◽  
The Central Nervous System ◽  
Metabolic Degradation ◽  
Distribution Studies

Peptide therapeutics offer numerous advantages in the treatment of diseases and disorders of the central nervous system (CNS). However, they are not without limitations, especially in terms of their pharmacokinetics where their metabolic lability and low blood–brain barrier penetration hinder their application. Targeted nanoparticle delivery systems are being tapped for their ability to improve the delivery of therapeutics into the brain non-invasively. We have developed a family of mannosylated glycoliposome delivery systems for targeted drug delivery applications. Herein, we demonstrate via in vivo distribution studies the potential of these glycoliposomes to improve the utility of CNS active therapeutics using dynantin, a potent and selective dynorphin peptide analogue antagonist of the kappa opioid receptor (KOR). Glycoliposomal entrapment protected dynantin against known rapid metabolic degradation and ultimately improved brain levels of the peptide by approximately 3–3.5-fold. Moreover, we linked this improved brain delivery with improved KOR antagonist activity by way of an approximately 30–40% positive modulation of striatal dopamine levels 20 min after intranasal administration. Overall, the results clearly highlight the potential of our glycoliposomes as a targeted delivery system for therapeutic agents of the CNS.

scholarly journals The Evolution of Safe and Effective Coaguligands for Vascular Targeting and Precision Thrombosis of Solid Tumors and Vascular Malformations

Biomedicines ◽  
2021 ◽  
Vol 9 (7) ◽  
pp. 776
Author(s):  
Fahimeh Faqihi ◽  
Marcus A. Stoodley ◽  
Lucinda S. McRobb
Keyword(s):  
Ischemic Stroke ◽  
Targeted Delivery ◽  
Vascular Malformations ◽  
Thrombus Formation ◽  
Developed Countries ◽  
Coagulation Cascade ◽  
Vascular Targeting ◽  
Systemic Delivery ◽  
Vessel Occlusion ◽  
Vessel Patency

In cardiovascular and cerebrovascular biology, control of thrombosis and the coagulation cascade in ischemic stroke, myocardial infarction, and other coagulopathies is the focus of significant research around the world. Ischemic stroke remains one of the largest causes of death and disability in developed countries. Preventing thrombosis and protecting vessel patency is the primary goal. However, utilization of the body’s natural coagulation cascades as an approach for targeted destruction of abnormal, disease-associated vessels and tissues has been increasing over the last 30 years. This vascular targeting approach, often termed “vascular infarction”, describes the deliberate, targeted delivery of a thrombogenic effector to diseased blood vessels with the aim to induce localized activation of the coagulation cascade and stable thrombus formation, leading to vessel occlusion and ablation. As systemic delivery of pro-thrombotic agents may cause consternation amongst traditional stroke researchers, proponents of the approach must suitably establish both efficacy and safety to take this field forward. In this review, we describe the evolution of this field and, with a focus on thrombogenic effectors, summarize the current literature with respect to emerging trends in “coaguligand” development, in targeted tumor vessel destruction, and in expansion of the approach to the treatment of brain vascular malformations.

scholarly journals A Maternal Smad Protein Regulates Early Embryonic Apoptosis in Xenopus laevis

2002 ◽  
Vol 22 (5) ◽  
pp. 1317-1328 ◽  
Author(s):  
Yuko Miyanaga ◽  
Ingrid Torregroza ◽  
Todd Evans
Keyword(s):  
Functional Analysis ◽  
Cell Survival ◽  
Caspase 3 ◽  
Embryonic Cell ◽  
Early Embryogenesis ◽  
Cell Cycles ◽  
Smad Proteins ◽  
Smad Protein ◽  
Smad Signaling Pathway ◽  
A Cell

ABSTRACT We identified cDNAs encoding the Xenopus Smad proteins most closely related to mammalian Smad8, and we present a functional analysis of this activity (also referred to recently as xSmad11). Misexpression experiments indicate that xSmad8(11) regulates pathways distinct from those regulated by the closely related xSmad1. Embryos that develop from eggs depleted of xSmad8(11) mRNA fail to gastrulate; instead, at the time of gastrulation, they initiate a widespread program of apoptosis, via a CPP32/caspase 3 pathway. Embryos that avoid this fate display gastrulation defects. Activation of apoptosis is rescued by expression of xSmad8(11) but not xSmad1. Our results demonstrate an embryonic requirement for Smad8(11) activity and show that a maternally derived Smad signaling pathway is required for gastrulation and for mediating a cell survival program during early embryogenesis. We suggest that xSmad8(11) functions as part of a maternally derived mechanism shown previously by others to monitor Xenopus early embryonic cell cycles.

scholarly journals Convection-enhanced delivery to the central nervous system

2015 ◽  
Vol 122 (3) ◽  
pp. 697-706 ◽  
Author(s):  
Russell R. Lonser ◽  
Malisa Sarntinoranont ◽  
Paul F. Morrison ◽  
Edward H. Oldfield
Keyword(s):  
Drug Delivery ◽  
Central Nervous System ◽  
Clinical Trials ◽  
Nervous System ◽  
Convective Flow ◽  
Clinical Applications ◽  
Systemic Delivery ◽  
Convection Enhanced Delivery ◽  
The Central Nervous System ◽  
Real Time Tracking

Convection-enhanced delivery (CED) is a bulk flow–driven process. Its properties permit direct, homogeneous, targeted perfusion of CNS regions with putative therapeutics while bypassing the blood-brain barrier. Development of surrogate imaging tracers that are co-infused during drug delivery now permit accurate, noninvasive real-time tracking of convective infusate flow in nervous system tissues. The potential advantages of CED in the CNS over other currently available drug delivery techniques, including systemic delivery, intrathecal and/or intraventricular distribution, and polymer implantation, have led to its application in research studies and clinical trials. The authors review the biophysical principles of convective flow and the technology, properties, and clinical applications of convective delivery in the CNS.

Microglia extracellular vesicles: focus on molecular composition and biological function

2021 ◽  
Vol 49 (4) ◽  
pp. 1779-1790 ◽  
Author(s):  
Lorenzo Ceccarelli ◽  
Chiara Giacomelli ◽  
Laura Marchetti ◽  
Claudia Martini
Keyword(s):  
Extracellular Vesicles ◽  
Molecular Mechanisms ◽  
Biological Function ◽  
Biological Effects ◽  
Genetic Material ◽  
Cell Communication ◽  
Molecular Composition ◽  
Cargo Proteins ◽  
A Cell ◽  
The Central Nervous System

Extracellular vesicles (EVs) are a heterogeneous family of cell-derived lipid bounded vesicles comprising exosomes and microvesicles. They are potentially produced by all types of cells and are used as a cell-to-cell communication method that allows protein, lipid, and genetic material exchange. Microglia cells produce a large number of EVs both in resting and activated conditions, in the latter case changing their production and related biological effects. Several actions of microglia in the central nervous system are ascribed to EVs, but the molecular mechanisms by which each effect occurs are still largely unknown. Conflicting functions have been ascribed to microglia-derived EVs starting from the neuronal support and ending with the propagation of inflammation and neurodegeneration, confirming the crucial role of these organelles in tuning brain homeostasis. Despite the increasing number of studies reported on microglia-EVs, there is also a lot of fragmentation in the knowledge on the mechanism at the basis of their production and modification of their cargo. In this review, a collection of literature data about the surface and cargo proteins and lipids as well as the miRNA content of EVs produced by microglial cells has been reported. A special highlight was given to the works in which the EV molecular composition is linked to a precise biological function.

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