scholarly journals Targeting Brain Disease in MPSII: Preclinical Evaluation of IDS-Loaded PLGA Nanoparticles

2019 ◽  
Vol 20 (8) ◽  
pp. 2014 ◽  
Author(s):  
Laura Rigon ◽  
Marika Salvalaio ◽  
Francesca Pederzoli ◽  
Elisa Legnini ◽  
Jason Thomas Duskey ◽  
...  
Keyword(s):  
Polymeric Nanoparticles ◽  
Plga Nanoparticles ◽  
Neurological Involvement ◽  
Lysosomal Storage ◽  
Enzyme Replacement ◽  
Organ Systems ◽  
General Improvement ◽  
The One ◽  
The Brain

Mucopolysaccharidosis type II (MPSII) is a lysosomal storage disorder due to the deficit of the enzyme iduronate 2-sulfatase (IDS), which leads to the accumulation of glycosaminoglycans in most organ-systems, including the brain, and resulting in neurological involvement in about two-thirds of the patients. The main treatment is represented by a weekly infusion of the functional enzyme, which cannot cross the blood-brain barrier and reach the central nervous system. In this study, a tailored nanomedicine approach based on brain-targeted polymeric nanoparticles (g7-NPs), loaded with the therapeutic enzyme, was exploited. Fibroblasts from MPSII patients were treated for 7 days with NPs loaded with the IDS enzyme; an induced IDS activity like the one detected in healthy cells was measured, together with a reduction of GAG content to non-pathological levels. An in vivo short-term study in MPSII mice was performed by weekly administration of g7-NPs-IDS. Biochemical, histological, and immunohistochemical evaluations of liver and brain were performed. The 6-weeks treatment produced a significant reduction of GAG deposits in liver and brain tissues, as well as a reduction of some neurological and inflammatory markers (i.e., LAMP2, CD68, GFAP), highlighting a general improvement of the brain pathology. The g7-NPs-IDS approach allowed a brain-targeted enzyme replacement therapy. Based on these positive results, the future aim will be to optimize NP formulation further to gain a higher efficacy of the proposed approach.

scholarly journals Exploiting the Potential of Drosophila Models in Lysosomal Storage Disorders: Pathological Mechanisms and Drug Discovery

Biomedicines ◽  
2021 ◽  
Vol 9 (3) ◽  
pp. 268
Author(s):  
Laura Rigon ◽  
Concetta De Filippis ◽  
Barbara Napoli ◽  
Rosella Tomanin ◽  
Genny Orso
Keyword(s):  
Negative Impact ◽  
Drug Repurposing ◽  
Lysosomal Storage Disorders ◽  
Neurological Involvement ◽  
Lysosomal Storage ◽  
Recombinant Enzymes ◽  
Enzyme Replacement ◽  
Storage Disorders ◽  
Drosophila Models

Lysosomal storage disorders (LSDs) represent a complex and heterogeneous group of rare genetic diseases due to mutations in genes coding for lysosomal enzymes, membrane proteins or transporters. This leads to the accumulation of undegraded materials within lysosomes and a broad range of severe clinical features, often including the impairment of central nervous system (CNS). When available, enzyme replacement therapy slows the disease progression although it is not curative; also, most recombinant enzymes cannot cross the blood-brain barrier, leaving the CNS untreated. The inefficient degradative capability of the lysosomes has a negative impact on the flux through the endolysosomal and autophagic pathways; therefore, dysregulation of these pathways is increasingly emerging as a relevant disease mechanism in LSDs. In the last twenty years, different LSD Drosophila models have been generated, mainly for diseases presenting with neurological involvement. The fruit fly provides a large selection of tools to investigate lysosomes, autophagy and endocytic pathways in vivo, as well as to analyse neuronal and glial cells. The possibility to use Drosophila in drug repurposing and discovery makes it an attractive model for LSDs lacking effective therapies. Here, ee describe the major cellular pathways implicated in LSDs pathogenesis, the approaches available for their study and the Drosophila models developed for these diseases. Finally, we highlight a possible use of LSDs Drosophila models for drug screening studies.

New Advanced Strategies for the Treatment of Lysosomal Diseases Affecting the Central Nervous System

2019 ◽  
Vol 25 (17) ◽  
pp. 1933-1950 ◽  
Author(s):  
Maria R. Gigliobianco ◽  
Piera Di Martino ◽  
Siyuan Deng ◽  
Cristina Casadidio ◽  
Roberta Censi
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Polymeric Nanoparticles ◽  
Genetic Diseases ◽  
Point Of View ◽  
Lysosomal Storage ◽  
Enzyme Replacement ◽  
Lysosomal Diseases ◽  
The Central Nervous System ◽  
Enzyme Delivery

Lysosomal Storage Disorders (LSDs), also known as lysosomal diseases (LDs) are a group of serious genetic diseases characterized by not only the accumulation of non-catabolized compounds in the lysosomes due to the deficiency of specific enzymes which usually eliminate these compounds, but also by trafficking, calcium changes and acidification. LDs mainly affect the central nervous system (CNS), which is difficult to reach for drugs and biological molecules due to the presence of the blood-brain barrier (BBB). While some therapies have proven highly effective in treating peripheral disorders in LD patients, they fail to overcome the BBB. Researchers have developed many strategies to circumvent this problem, for example, by creating carriers for enzyme delivery, which improve the enzyme’s half-life and the overexpression of receptors and transporters in the luminal or abluminal membranes of the BBB. This review aims to successfully examine the strategies developed during the last decade for the treatment of LDs, which mainly affect the CNS. Among the LD treatments, enzyme-replacement therapy (ERT) and gene therapy have proven effective, while nanoparticle, fusion protein, and small molecule-based therapies seem to offer considerable promise to treat the CNS pathology. This work also analyzed the challenges of the study to design new drug delivery systems for the effective treatment of LDs. Polymeric nanoparticles and liposomes are explored from their technological point of view and for the most relevant preclinical studies showing that they are excellent choices to protect active molecules and transport them through the BBB to target specific brain substrates for the treatment of LDs.

scholarly journals Stability and ocular biodistribution of topically administered PLGA nanoparticles

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Sean Swetledge ◽  
Renee Carter ◽  
Rhett Stout ◽  
Carlos E. Astete ◽  
Jangwook P. Jung ◽  
...  
Keyword(s):  
Uv Light ◽  
Light Exposure ◽  
Polymeric Nanoparticles ◽  
Plga Nanoparticles ◽  
Eye Disease ◽  
Control Group ◽  
Eye Tissues ◽  
Nanoparticle Morphology ◽  
The Stability

AbstractPolymeric nanoparticles have been investigated as potential delivery systems for therapeutic compounds to address many ailments including eye disease. The stability and spatiotemporal distribution of polymeric nanoparticles in the eye are important regarding the practical applicability and efficacy of the delivery system in treating eye disease. We selected poly(lactic-co-glycolic acid) (PLGA) nanoparticles loaded with lutein, a carotenoid antioxidant associated with eye health, as our model ophthalmic nanodelivery system and evaluated its stability when suspended in various conditions involving temperature and light exposure. We also assessed the ocular biodistribution of the fluorescently labeled nanoparticle vehicle when administered topically. Lutein-loaded nanoparticles were stable in suspension when stored at 4 °C with only 26% lutein release and no significant lutein decay or changes in nanoparticle morphology. When stored at 25 °C and 37 °C, these NPs showed signs of bulk degradation, had significant lutein decay compared to 4 °C, and released over 40% lutein after 5 weeks in suspension. Lutein-loaded nanoparticles were also more resistant to photodegradation compared to free lutein when exposed to ultraviolet (UV) light, decaying approximately 5 times slower. When applied topically in vivo, Cy5-labled nanoparticles showed high uptake in exterior eye tissues including the cornea, episcleral tissue, and sclera. The choroid was the only inner eye tissue that was significantly higher than the control group. Decreased fluorescence in all exterior eye tissues and the choroid at 1 h compared to 30 min indicated rapid elimination of nanoparticles from the eye.

scholarly journals Extracellular Vesicles as Drug Carriers for Enzyme Replacement Therapy to Treat CLN2 Batten Disease: Optimization of Drug Administration Routes

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1273 ◽  
Author(s):  
Matthew J. Haney ◽  
Yuling Zhao ◽  
Yeon S. Jin ◽  
Elena V. Batrakova
Keyword(s):  
Mouse Model ◽  
Extracellular Vesicles ◽  
Broad Class ◽  
Batten Disease ◽  
Drug Carriers ◽  
Lysosomal Storage ◽  
Storage Material ◽  
Enzyme Replacement ◽  
Daunting Task ◽  
The Brain

CLN2 Batten disease (BD) is one of a broad class of lysosomal storage disorders that is characterized by the deficiency of lysosomal enzyme, TPP1, resulting in a build-up of toxic intracellular storage material in all organs and subsequent damage. A major challenge for BD therapeutics is delivery of enzymatically active TPP1 to the brain to attenuate progressive loss of neurological functions. To accomplish this daunting task, we propose the harnessing of naturally occurring nanoparticles, extracellular vesicles (EVs). Herein, we incorporated TPP1 into EVs released by immune cells, macrophages, and examined biodistribution and therapeutic efficacy of EV-TPP1 in BD mouse model, using various routes of administration. Administration through intrathecal and intranasal routes resulted in high TPP1 accumulation in the brain, decreased neurodegeneration and neuroinflammation, and reduced aggregation of lysosomal storage material in BD mouse model, CLN2 knock-out mice. Parenteral intravenous and intraperitoneal administrations led to TPP1 delivery to peripheral organs: liver, kidney, spleen, and lungs. A combination of intrathecal and intraperitoneal EV-TPP1 injections significantly prolonged lifespan in BD mice. Overall, the optimization of treatment strategies is crucial for successful applications of EVs-based therapeutics for BD.

Uptake and processing of glycoproteins by rat hepatic mannose receptor

1987 ◽  
Vol 252 (5) ◽  
pp. E690-E698 ◽  
Author(s):  
M. E. Taylor ◽  
M. S. Leaning ◽  
J. A. Summerfield
Keyword(s):  
Intracellular Transport ◽  
Compartmental Model ◽  
Mannose Receptor ◽  
Structural Features ◽  
Hepatic Uptake ◽  
The Other ◽  
Lysosomal Storage ◽  
Sinusoidal Cells ◽  
Enzyme Replacement

A linear compartmental model has been developed for the in vivo metabolism of glycoproteins. The model is applied to the interpretation of dynamic data from the rat on agalactoorosomucoid (AGOR), an N-acetylglucosamine (GlcNAc-)-terminated glycoprotein, and three neoglycoproteins terminating in mannose [mannose36-bovine serum albumin (Man-BSA)] or glucose [maltose29-BSA (Mal29-BSA) and maltose8-BSA (Mal8-BSA)]. All of these proteins are taken up by the Man/GlcNAc receptor on hepatic sinusoidal cells. The rate of uptake was found to be determined by sugar type (Man-BSA, 0.78 min-1 greater than Mal29-BSA, 0.13 min-1), sugar density (Mal29-BSA greater than Mal8-BSA), and the geometry of the sugar display (AGOR, 0.51 min-1 greater than Mal29-BSA). Intracellular transport from the cell membrane to the lysosomes was slower for Man-BSA (approximately 3 min) than for the other ligands (approximately 0 min), suggesting that receptor-ligand uncoupling was slower for Man-BSA for which the receptor had the highest affinity or that extralysosomal catabolism of the other ligands occurred. Catabolism was also determined by the carbohydrate moiety of the ligand; it was greater for Mal29-BSA and Mal8-BSA (greater than or equal to 0.8 min-1) than for Man-BSA (0.27 min-1), and AGOR, with a complex oligosaccharide, was most resistant to degradation (0.14 min-1). An understanding of these structural features of glycoproteins that influence hepatic uptake, transport, and catabolism will be of value in drug targeting and for enzyme replacement in lysosomal storage disorders.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Amphotericin B-loaded mannose modified poly(d,l-lactide-co-glycolide) polymeric nanoparticles for the treatment of visceral leishmaniasis: in vitro and in vivo approaches

RSC Advances ◽  
2017 ◽  
Vol 7 (47) ◽  
pp. 29575-29590 ◽  
Author(s):  
Santanu Ghosh ◽  
Suman Das ◽  
Asit Kumar De ◽  
Nabanita Kar ◽  
Tanmoy Bera
Keyword(s):  
Visceral Leishmaniasis ◽  
Amphotericin B ◽  
Polymeric Nanoparticles ◽  
Plga Nanoparticles

Amphotericin B-loaded mannose modified PLGA nanoparticles are more efficacious in the treatment of visceral leishmaniasis in bothin vitroandin vivomodels than unmodified nanoformulations.

scholarly journals Migration-based selections of antibodies that convert bone marrow into trafficking microglia-like cells that reduce brain amyloid β

2018 ◽  
Vol 115 (3) ◽  
pp. E372-E381 ◽  
Author(s):  
Kyung Ho Han ◽  
Britni M. Arlian ◽  
Matthew S. Macauley ◽  
James C. Paulson ◽  
Richard A. Lerner
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Amyloid Β ◽  
Plaque Formation ◽  
Selection System ◽  
Organ Systems ◽  
A Cell ◽  
The Brain ◽  
Different Tissues

One goal of regenerative medicine is to repair damaged tissue. This requires not only generating new cells of the proper phenotype, but also selecting for those that properly integrate into sites of injury. In our laboratory we are using a cell-migration–based in vivo selection system to generate antibodies that induce cells to both differentiate and selectively localize to different tissues. Here we describe an antibody that induces bone marrow stem cells to differentiate into microglia-like cells that traffic to the brain where they organize into typical networks. Interestingly, in the APP/PS1 Alzheimer’s disease mouse model, these induced microglia-like cells are found at sites of plaque formation and significantly reduce their number. These results raise the intriguing question as to whether one can use such antibody-induced differentiation of stem cells to essentially recapitulate embryogenesis in adults to discover cells that can regenerate damaged organ systems.

scholarly journals Neuroinvasion of SARS-CoV-2 in human and mouse brain

2021 ◽  
Vol 218 (3) ◽  
Author(s):  
Eric Song ◽  
Ce Zhang ◽  
Benjamin Israelow ◽  
Alice Lu-Culligan ◽  
Alba Vieites Prado ◽  
...  
Keyword(s):  
Cortical Neurons ◽  
Immune Cell ◽  
Multiple Organ ◽  
Type I ◽  
Organ Systems ◽  
The Central Nervous System ◽  
Interferon Responses ◽  
The Brain ◽  
Immune Cell Infiltrates

Although COVID-19 is considered to be primarily a respiratory disease, SARS-CoV-2 affects multiple organ systems including the central nervous system (CNS). Yet, there is no consensus on the consequences of CNS infections. Here, we used three independent approaches to probe the capacity of SARS-CoV-2 to infect the brain. First, using human brain organoids, we observed clear evidence of infection with accompanying metabolic changes in infected and neighboring neurons. However, no evidence for type I interferon responses was detected. We demonstrate that neuronal infection can be prevented by blocking ACE2 with antibodies or by administering cerebrospinal fluid from a COVID-19 patient. Second, using mice overexpressing human ACE2, we demonstrate SARS-CoV-2 neuroinvasion in vivo. Finally, in autopsies from patients who died of COVID-19, we detect SARS-CoV-2 in cortical neurons and note pathological features associated with infection with minimal immune cell infiltrates. These results provide evidence for the neuroinvasive capacity of SARS-CoV-2 and an unexpected consequence of direct infection of neurons by SARS-CoV-2.

scholarly journals Differences in MPS I and MPS II Disease Manifestations

2021 ◽  
Vol 22 (15) ◽  
pp. 7888
Author(s):  
Christiane S. Hampe ◽  
Brianna D. Yund ◽  
Paul J. Orchard ◽  
Troy C. Lund ◽  
Jacob Wesley ◽  
...  
Keyword(s):  
Dermatan Sulfate ◽  
Treatment Options ◽  
Neurological Involvement ◽  
Type I ◽  
Ionic Balance ◽  
Lysosomal Storage ◽  
Enzyme Replacement ◽  
Mps Ii ◽  
Corneal Clouding ◽  
Mps I

Mucopolysaccharidosis (MPS) type I and II are two closely related lysosomal storage diseases associated with disrupted glycosaminoglycan catabolism. In MPS II, the first step of degradation of heparan sulfate (HS) and dermatan sulfate (DS) is blocked by a deficiency in the lysosomal enzyme iduronate 2-sulfatase (IDS), while, in MPS I, blockage of the second step is caused by a deficiency in iduronidase (IDUA). The subsequent accumulation of HS and DS causes lysosomal hypertrophy and an increase in the number of lysosomes in cells, and impacts cellular functions, like cell adhesion, endocytosis, intracellular trafficking of different molecules, intracellular ionic balance, and inflammation. Characteristic phenotypical manifestations of both MPS I and II include skeletal disease, reflected in short stature, inguinal and umbilical hernias, hydrocephalus, hearing loss, coarse facial features, protruded abdomen with hepatosplenomegaly, and neurological involvement with varying functional concerns. However, a few manifestations are disease-specific, including corneal clouding in MPS I, epidermal manifestations in MPS II, and differences in the severity and nature of behavioral concerns. These phenotypic differences appear to be related to different ratios between DS and HS, and their sulfation levels. MPS I is characterized by higher DS/HS levels and lower sulfation levels, while HS levels dominate over DS levels in MPS II and sulfation levels are higher. The high presence of DS in the cornea and its involvement in the arrangement of collagen fibrils potentially causes corneal clouding to be prevalent in MPS I, but not in MPS II. The differences in neurological involvement may be due to the increased HS levels in MPS II, because of the involvement of HS in neuronal development. Current treatment options for patients with MPS II are often restricted to enzyme replacement therapy (ERT). While ERT has beneficial effects on respiratory and cardiopulmonary function and extends the lifespan of the patients, it does not significantly affect CNS manifestations, probably because the enzyme cannot pass the blood–brain barrier at sufficient levels. Many experimental therapies, therefore, aim at delivery of IDS to the CNS in an attempt to prevent neurocognitive decline in the patients.

PLA/PLGA nanoparticles for delivery of drugs across the blood-brain barrier

2013 ◽  
Vol 2 (3) ◽  
pp. 241-257 ◽  
Author(s):  
Jingyan Li ◽  
Cristina Sabliov
Keyword(s):  
Drug Delivery ◽  
Blood Brain Barrier ◽  
Polymeric Nanoparticles ◽  
Drug Carrier ◽  
Plga Nanoparticles ◽  
Brain Barrier ◽  
Poly Lactic Acid ◽  
Blood Brain

AbstractThe blood-brain barrier (BBB), which protects the central nervous system (CNS) from unnecessary substances, is a challenging obstacle in the treatment of CNS disease. Many therapeutic agents such as hydrophilic and macromolecular drugs cannot overcome the BBB. One promising solution is the employment of polymeric nanoparticles (NPs) such as poly (lactic-co-glycolic acid) (PLGA) NPs as drug carrier. Over the past few years, significant breakthroughs have been made in developing suitable PLGA and poly (lactic acid) (PLA) NPs for drug delivery across the BBB. Recent advances on PLGA/PLA NPs enhanced neural delivery of drugs are reviewed in this paper. Both in vitro and in vivo studies are included. In these papers, enhanced cellular uptake and therapeutic efficacy of drugs delivered with modified PLGA/PLA NPs compared with free drugs or drugs delivered by unmodified PLGA/PLA NPs were shown; no significant in vitro cytotoxicity was observed for PLGA/PLA NPs. Surface modification of PLGA/PLA NPs by coating with surfactants/polymers or covalently conjugating the NPs with targeting ligands has been confirmed to enhance drug delivery across the BBB. Most unmodified PLGA NPs showed low brain uptake (<1%), which indirectly confirms the safety of PLGA/PLA NPs used for other purposes than treating CNS diseases.

Sign in / Sign up

Export Citation Format

Share Document