Exosomes and the blood–brain Barrier: Implications for Neurological Diseases
2011; Future Science Ltd; Volume: 2; Issue: 9 Linguagem: Inglês
10.4155/tde.11.83
ISSN2041-6008
AutoresMatthew J. A. Wood, Aisling J. O’Loughlin, Samira Lakhal,
Tópico(s)RNA regulation and disease
ResumoTherapeutic DeliveryVol. 2, No. 9 EditorialFree AccessExosomes and the blood–brain barrier: implications for neurological diseasesMatthew JA Wood, Aisling J O'Loughlin & Samira LakhalMatthew JA Wood† Author for correspondenceDepartment of Physiology, Anatomy & Genetics, University of Oxford, South Parks Road, Oxford, OX1 3QX, UK. , Aisling J O'LoughlinDepartment of Physiology, Anatomy & Genetics, University of Oxford, UK & Samira LakhalDepartment of Physiology, Anatomy & Genetics, University of Oxford, UKPublished Online:14 Sep 2011https://doi.org/10.4155/tde.11.83AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInRedditEmail Keywords: antibodyblood–brain barrierexosomegene therapyneurodegenerationRNAisiRNASuccessful delivery of macromolecular therapeutic agents across the blood–brain barrier (BBB) to the CNS is a major challenge in the treatment of neurological disease. Recently, the exploitation of natural nanoparticles known as exosomes has been pioneered and demonstrates their potential as therapeutic delivery vehicles. The natural macromolecular delivery and targeting properties of exosomes are well exemplified with siRNA delivery systemically to the brain. Moreover, delivery of exosomes appears to be well tolerated. This novel natural nanotechnology, therefore, has potential for systemic drug delivery across the BBB to treat a range of neurological conditions.The blood–brain barrierThe development of therapeutics for targets within the CNS has been hindered by the inability of macromolecular drugs with proven in vitro efficacy to cross the BBB.The BBB is a dynamic and complex physical barrier between the brain and the peripheral circulation that regulates the influx and efflux of molecules to the brain to preserve CNS homeostasis and maintains the stable local ionic microenvironment necessary for neuronal function. It consists of a sealed monolayer of endothelial cells surrounding capillaries. These endothelial cells interact and associate closely with the basement membrane as well as astrocytes and pericytes [1,2]. Endothelial cells and the tight junctions between them are relatively impermeable and block diffusion of molecules across membranes, inhibiting their passage into the brain. Although most large molecules over 400 Da and with more than nine hydrogen bonds cannot pass [3], nutrients can reach the brain by specific transport systems. While the BBB shields the brain microenvironment from potentially toxic substances in the circulation, it also represents the greatest obstacle to the delivery of drugs for the treatment of disorders of the CNS [4].Neurodegenerative disorders, such as Alzheimer's, Parkinson's and Huntington's disease are among the most costly in terms of quality of life, financial and social costs. Due to increasing life expectancy rates throughout the western world, the number of people with a neurodegenerative or other neurological disorder is likely to increase. The World Health Organization predicts that by 2040, neurodegenerative diseases will surpass cancer as the second leading cause of death, following cardiovascular disease, and the annual cost of Alzheimer's alone in the UK is estimated at UK£17 billion [101]. Currently, treatments available for these disorders are aimed merely at symptom management. However, research into the pathophysiology of these diseases is elucidating mechanisms that could be responsible, and targets are being identified for the development of small-molecule and large macromolecular drugs. The translation of these therapeutic compounds from a preclinical stage into viable treatments is hampered by the inability to deliver these substances across the BBB, highlighting the need for drug delivery vehicles that surmount the BBB.To date, a number of techniques have been utilized for drug delivery to the brain. These include transport via passive partitioning, solute carriers, transport of polar molecules via specific carriers (e.g., ABC transporters), transcytosis of macromolecules, and invasive approaches including neurosurgery, direct delivery via the olfactory route and osmotic/biochemical opening of the BBB, but these are associated with low efficacy and safety issues [4,5]. In recent years major advances in the field of gene therapy and the use of nucleic acids and their analogues to target genes of interest in vivo has emphasized the need for a universal vehicle to deliver these large-weight hydrophilic molecules across the BBB. Viral vectors and liposomes have been used for this purpose, but are associated with side effects such as toxicity and immunogenicity. The latest developments, highlighted in the work by Alvarez-Erviti et al. harness a natural carrier system – exosomes – and show that they hold great promise as a safe and efficient means of targeting the brain and penetrating the BBB [6].What are exosomes?Exosomes were first described in sheep reticulocytes where they were shown to externalize the transferrin receptor. These natural biological nanovesicles were seen as round particles of approximately 50 nm diameter, within multivesicular bodies [7,8], which are formed by inward budding of the membrane of late endosomes. When the membrane of the multivesicular body fuses with the cell membrane, these vesicles, known as exosomes, are released into the extracellular space. As a result, proteins and lipids on the exosomal surface retain the same orientation as on the cell membrane.Exosomes are distinguishable from other microvesicles and microparticles, including apoptotic blebs or those released by direct budding of the cell membrane, by their size (between 40 and 100 nm), absence of organelles and high levels of sphingomyelin, cholesterol and GM3 glycolipid in their membranes [9]. They are secreted from many different cell types, including immune cells such as B cells, T cells and dendritic cells – where they can aid in antigen presentation [10] – mast cells, platelets, as well as neurons and epithelial cells and are also present in biological fluids including plasma, urine, malignant effusions, bronchoalveolar lavage fluid, breast milk, saliva, synovial fluid and amniotic fluid [11,12].Exosomes as macromolecular transportersArguably the most interesting finding regarding exosomes has come from transcriptomic and proteomic analysis of human and murine mast cells, demonstrating that they act as natural transporters of RNA and protein [13]. Proteomic analysis has been performed on exosomes from different sources and although there are some proteins that appear to be common to all exosomes studied to date (e.g., LAMP1, LAMP2 and ALIX) and are routinely used as exosomal markers, there are also proteins that are specific to exosomes from particular parent cells [11]. In addition, 1300 mRNAs and 120 miRNAs have been identified in exosomes from mast cells, many of which were not detected in the cytoplasm of the parent cells [13]. There is evidence that the proteins AGO2 and GW182, which are components of the RNA-induced silencing complex, can influence miRNA loading into exosomes [14]. This exosomal mRNA can participate in de novo protein synthesis in the recipient cell, which suggests that exosomes participate in cell–cell communication and the horizontal transfer of genetic information [13].Due to their release from many cell types and presence in biological fluids, exosomes have been reported to be involved in many cellular functions including protein secretion, immune response regulation, antigen presentation, RNA and protein transfer, transmission of infectious cargo and cell–cell signaling [11]. Exosomes may potentially function at a close range and also at a distance through transfer in biological fluids such as plasma.Therapeutic uses of exosomesSome unmodified exosomes may have intrinsic therapeutic value. Secretions from mesenchymal stem cells (MSCs) have been shown to ameliorate myocardial infarction/reperfusion injury and reduce infarct size in mouse models [15]. It has since been shown that this cardioprotective effect is due to the secretion of exosomes from MSCs. In addition, exosomes have been tested in Phase I clinical trials for melanoma and lung cancer – patients with late-stage non-small-cell lung cancer and in a separate study, melanoma, were injected with dendritic cell-derived exosomes [16,17]. The treatments were well-tolerated and the exosomes mediated antigen presentation and activated natural killer cells to induce anti-tumor responses [18].Exosomes also hold great promise as potential diagnostic tools as they are released by tumor cells and contain tumor protein biomarkers such as a variant of the EGF receptor in glioblastoma [19]. It has also been suggested that they could potentially be used to screen asymptomatic populations because research has uncovered a conserved miRNA profile in exosomes derived from patients with tumors [20]. As well as their beneficial effects on tumors, exosomes have been shown to reduce inflammation in animal models of arthritis by modulating the immune system, and could therefore have potential to treat autoimmune disorders [21].While unmodified exosomes may have intrinsic beneficial value in some disease conditions, they are also an attractive option as a vehicle for delivery of therapeutic cargo. Their potential as delivery vectors has been assessed by testing their ability to transport exogenous oligonucleotides to specific target tissues. Work described in Alvarez-Erviti et al. provided the first proof of this concept [6]. Immature dendritic cells were harvested from mouse bone marrow and used to generate immunologically inert exosomes without lymphocyte stimulatory factors such as CD80, CD86 and MHCII. A series of ultracentrifugation steps were used to purify the exosomes to establish a pool with uniform biophysical properties, which were then characterized by electron microscopy and nanoparticle tracking analysis technology, loaded with siRNA for GAPDH, cyclophilin and BACE1, the latter of which is a target gene known to be a therapeutic involved in the pathogenesis in Alzheimer's disease as it is one of the enzymes that cleaves amyloid precursor protein to release amyloidogenic Aβ42. Exosomes loaded with siRNA were then added to Neuro2A cells for in vitro testing and in vivo by tail vein injection. In order to facilitate targeting to the brain and reduce the risk of off-target effects following systemic injection, a targeting strategy was employed. Dendritic cells were transfected with a plasmid expressing a rabies virus glycoprotein (RVG) peptide known to selectively target the nicotinic acetylcholine receptor in neurons. This peptide was cloned into the extracellular N-terminus of Lamp2b, an exosomal membrane surface marker, to ensure that the RVG peptide was displayed on the surface of exosomes. Electroporation techniques were found to be more efficient than transfection and were used to load the exosomes with siRNA. Following tail vein injection, a 60% knockdown at RNA and protein level was achieved only in the brain. The siRNA was fluorescently labeled and detected in the target tissue by fluorescence microscopy. In vivo, knockdown was achieved in the midbrain, cortex and striatum. Expression was confirmed by qPCR. There was no significant knockdown in liver or kidney, organs associated with drug clearance. A reduction in β-amyloid could be detected in the brain cortex of animals injected with BACE-1 siRNA-loaded RVG exosomes. Moreover, the exosomes were well-tolerated in terms of toxicity. Inflammatory cytokine markers were monitored and did not significantly change, nor were T lymphocytes stimulated, even following repeated exposure. This work demonstrates the efficacy and in vivo safety of exosomes as a therapeutic delivery vector that can surmount the BBB.ConclusionThe discovery of exosomes and their use as a potential therapeutic delivery system signals a dramatic leap and paradigm shift in the field of gene therapy. Further work is necessary to translate these findings into clinical applications. Research on generating an expandable exosome source will be crucial to further developments in this field. As raised by Alvarez-Erviti et al., it will be important to examine the effects on recipient cells of nucleic acids and proteins incorporated into exosomes from the parent cell. The low immunogenicity and potential to load and deliver them in a cell type-specific manner is vital for gene therapy. It will be necessary to determine how exosomes are incorporated into cells following targeting in order to gain insight into their biology and enable knowledge-based targeting strategies.The exploitation of these natural delivery vehicles holds great promise as a breakthrough for drug delivery. If the supporting technologies can be generated, the ability of exosomes to encapsulate and deliver drugs and genetic material across biological barriers could revolutionize the field of gene therapy and heralds a new era in the treatment of neurological disorders.Future perspectiveIn order to realize the therapeutic potential of exosomes for neurological diseases, it is necessary to determine how they cross the BBB, and to improve on methods for isolation, loading, characterization and targeting to different cell types.Since exosomes are produced from different cell types, the best parental cell source needs to be investigated. Dendritic cells and MSCs are used currently, but induced pluripotent stem cells hold great promise as they are long lived, can be stored and derived from patient fibroblasts with a lower risk of immune rejection. Furthermore, these cells can be differentiated along a neuronal lineage in vitro and it is thought that exosomes from these cells might have inherent brain-targeting efficiency. In addition, recent work involving transfection of MSCs with an oncogene to generate an immortal population of cells from which exosomes can be derived could provide an expandable source [22]. Initial indications are that it does not alter the therapeutic potential of these exosomes; however, the risk of transfer of the oncogene to target cells must be investigated further.Isolation and purification procedures can vary depending on the tissue from which the exosomes are derived, but need to be standardized to allow for comparison. In order to prevent contamination of exosomal preparations with retroviruses due to their similar size and densities, other methods such as immunoaffinity capture may be required. Techniques of serial centrifugation, linear sucrose gradients, affinity capture using magnetic beads have been used to purify exosomes [11], but a combination of ultrafilatration and ultracentrifugation were necessary in the aforementioned clinical trials to obtain clinical grade preparations. Loading of drug cargoes into the exosomes must be improved to increase efficiency and also expand the cargo repertoire. Targeting efficiency and specificity needs to be improved by exploring novel and known peptides and other methods including the use of antibody targeting.Interestingly, exosomes also play a direct role in disease pathology, including HIV [23], cancer [19], and the autoimmune disorder rheumatoid arthritis [24]. Furthermore, exosomes have been implicated in CNS pathologies including prion diseases [25], Parkinson's disease and Alzheimer's disease. Exosomes may directly transfer α-synuclein between cells and thus contribute to the propagation of Parkinson's disease pathology [26]. This has been shown to occur in vitro in cells that overexpress α-synuclein. The effect is potentiated upon generation of the lysosomal dysfunction found in Parkinson's disease, which stimulated more α-synuclein to be released within exosomes and transmitted to recipient cells. α-synuclein derived from exosomes can cause the death of the recipient cell [27]. Exosomal proteins have been identified in the plaques of Alzheimer's disease brains, which indicates they may be involved in the pathogenesis of this common neurodgenerative disorder [28]. C-terminal fragments of amyloid precursor protein and Aβ itself, as well as the enzymes responsible for the amyloidogenic cleavage of amyloid precursor protein have been found within exosomes [29]. Any potential side effects associated with these pathological issues need to be investigated further.Financial & competing interests disclosureMatthew Wood has patents pending related to therapeutic exosome delivery technology. Matthew Wood has received funding support from Novartis Pharmaceuticals in support of this work. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.No writing assistance was utilized in the production of this manuscript.Bibliography1 Armulik A, Genové G, Mäe M et al. Pericytes regulate the blood–brain barrier. 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Part II: Intercellular neuronal cell-to-cell transportJournal of Controlled Release, Vol. 177Stimulatory Effect of Whole Coffee Fruit Concentrate Powder on Plasma Levels of Total and Exosomal Brain-Derived Neurotrophic Factor in Healthy Subjects: An Acute Within-Subject Clinical StudyFood and Nutrition Sciences, Vol. 04, No. 09 Vol. 2, No. 9 Follow us on social media for the latest updates Metrics Downloaded 8,278 times History Published online 14 September 2011 Published in print September 2011 Information© Future Science LtdKeywordsantibodyblood–brain barrierexosomegene therapyneurodegenerationRNAisiRNAFinancial & competing interests disclosureMatthew Wood has patents pending related to therapeutic exosome delivery technology. Matthew Wood has received funding support from Novartis Pharmaceuticals in support of this work. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.No writing assistance was utilized in the production of this manuscript.PDF download
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