TPP1 Delivery to Lysosomes with Extracellular Vesicles and their Enhanced Brain Distribution in the Animal Model of Batten Disease

Extracellular vesicles (EVs) are promising natural nanocarriers for delivery of various types of therapeutics. Earlier engineered EV‐based formulations for neurodegenerative diseases and cancer are reported. Herein, the use of macrophage‐derived EVs for brain delivery of a soluble lysosomal enzyme tripeptidyl peptidase‐1, TPP1, to treat a lysosomal storage disorder, Neuronal Ceroid Lipofuscinoses 2 (CLN2) or Batten disease, is investigated. TPP1 is loaded into EVs using two methods: i) transfection of parental EV‐producing macrophages with TPP1‐encoding plasmid DNA (pDNA) or ii) incorporation therapeutic protein TPP1 into naive empty EVs. For the former approach, EVs released by pretransfected macrophages contain the active enzyme and TPP1‐encoding pDNA. To achieve high loading efficiency by the latter approach, sonication or permeabilization of EV membranes with saponin is utilized. Both methods provide proficient incorporation of functional TPP1 into EVs (EV‐TPP1). EVs significantly increase stability of TPP1 against protease degradation and provide efficient TPP1 delivery to target cells in in vitro model of CLN2. The majority of EV‐TPP1 (≈70%) is delivered to target organelles, lysosomes. Finally, a robust brain accumulation of EV carriers and increased lifespan is recorded in late‐infantile neuronal ceroid lipofuscinosis (LINCL) mouse model following intraperitoneal administration of EV‐TPP1.

[1]  R. Desnick,et al.  Enzyme replacement and enhancement therapies: lessons from lysosomal disorders , 2002, Nature Reviews Genetics.

[2]  Danielle A. Simmons,et al.  Postnatal development of inflammation in a murine model of Niemann–Pick type C disease: immunohistochemical observations of microglia and astroglia , 2003, Experimental Neurology.

[3]  R. Sidman,et al.  A Mouse Model of Classical Late-Infantile Neuronal Ceroid Lipofuscinosis Based on Targeted Disruption of the CLN2 Gene Results in a Loss of Tripeptidyl-Peptidase I Activity and Progressive Neurodegeneration , 2004, The Journal of Neuroscience.

[4]  W. Sly,et al.  Developmentally regulated mannose 6-phosphate receptor-mediated transport of a lysosomal enzyme across the blood-brain barrier. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[5]  Aled Clayton,et al.  Isolation and Characterization of Exosomes from Cell Culture Supernatants and Biological Fluids , 2006, Current protocols in cell biology.

[6]  F. Cordelières,et al.  A guided tour into subcellular colocalization analysis in light microscopy , 2006, Journal of microscopy.

[7]  E. Alnemri,et al.  AIM2 activates the inflammasome and cell death in response to cytoplasmic DNA , 2009, Nature.

[8]  C. Théry,et al.  Membrane vesicles as conveyors of immune responses , 2009, Nature Reviews Immunology.

[9]  H. Gendelman,et al.  Macrophage delivery of therapeutic nanozymes in a murine model of Parkinson's disease. , 2010, Nanomedicine.

[10]  Dongmei Sun,et al.  A novel nanoparticle drug delivery system: the anti-inflammatory activity of curcumin is enhanced when encapsulated in exosomes. , 2010, Molecular therapy : the journal of the American Society of Gene Therapy.

[11]  G. Silva.  Nanotechnology applications and approaches for neuroregeneration and drug delivery to the central nervous system , 2010, Annals of the New York Academy of Sciences.

[12]  S. Mole,et al.  Therapeutic approaches to the challenge of neuronal ceroid lipofuscinoses. , 2011, Current pharmaceutical biotechnology.

[13]  H. Gendelman,et al.  Cell-mediated transfer of catalase nanoparticles from macrophages to brain endothelial, glial and neuronal cells. , 2011, Nanomedicine.

[14]  J. Kwekkeboom,et al.  Hepatic cell-to-cell transmission of small silencing RNA can extend the therapeutic reach of RNA interference (RNAi) , 2011, Gut.

[15]  H. Gendelman,et al.  Polyelectrolyte complex optimization for macrophage delivery of redox enzyme nanoparticles. , 2011, Nanomedicine.

[16]  Dongmei Sun,et al.  Treatment of brain inflammatory diseases by delivering exosome encapsulated anti-inflammatory drugs from the nasal region to the brain. , 2011, Molecular therapy : the journal of the American Society of Gene Therapy.

[17]  M. Zöller,et al.  Toward tailored exosomes: the exosomal tetraspanin web contributes to target cell selection. , 2012, The international journal of biochemistry & cell biology.

[18]  X. Breakefield,et al.  Microvesicle-associated AAV vector as a novel gene delivery system. , 2012, Molecular therapy : the journal of the American Society of Gene Therapy.

[19]  Yi Li,et al.  Exosome‐Mediated Transfer of miR‐133b from Multipotent Mesenchymal Stromal Cells to Neural Cells Contributes to Neurite Outgrowth , 2012, Stem cells.

[20]  Jian-Bing Fan,et al.  miR-1289 and “Zipcode”-like Sequence Enrich mRNAs in Microvesicles , 2012, Molecular therapy. Nucleic acids.

[21]  M. Wood,et al.  Exosomes and microvesicles: extracellular vesicles for genetic information transfer and gene therapy. , 2012, Human molecular genetics.

[22]  H. Gendelman,et al.  Blood-borne macrophage-neural cell interactions hitchhike on endosome networks for cell-based nanozyme brain delivery. , 2012, Nanomedicine.

[23]  Per Sunnerhagen,et al.  Plasma exosomes can deliver exogenous short interfering RNA to monocytes and lymphocytes , 2012, Nucleic acids research.

[24]  J. Cooper,et al.  Synergistic effects of central nervous system‐directed gene therapy and bone marrow transplantation in the murine model of infantile neuronal ceroid lipofuscinosis , 2012, Annals of neurology.

[25]  Frances M. Platt,et al.  Lysosomal storage disorders: The cellular impact of lysosomal dysfunction , 2012, The Journal of cell biology.

[26]  Keith L Ligon,et al.  Delivery of Functional Anti-miR-9 by Mesenchymal Stem Cell–derived Exosomes to Glioblastoma Multiforme Cells Conferred Chemosensitivity , 2013, Molecular therapy. Nucleic acids.

[27]  Michael Chopp,et al.  Exosomes from marrow stromal cells expressing miR-146b inhibit glioma growth. , 2013, Cancer letters.

[28]  M. V. Filatov,et al.  Exosomes are natural carriers of exogenous siRNA to human cells in vitro , 2013, Cell Communication and Signaling.

[29]  H. Gendelman,et al.  Specific Transfection of Inflamed Brain by Macrophages: A New Therapeutic Strategy for Neurodegenerative Diseases , 2013, PloS one.

[30]  T. Ochiya,et al.  Systemically injected exosomes targeted to EGFR deliver antitumor microRNA to breast cancer cells. , 2013, Molecular therapy : the journal of the American Society of Gene Therapy.

[31]  S. Lim,et al.  Exosomes for drug delivery - a novel application for the mesenchymal stem cell. , 2013, Biotechnology advances.

[32]  Shu Zhang,et al.  Preformed albumin corona, a protective coating for nanoparticles based drug delivery system. , 2013, Biomaterials.

[33]  Jaesung Park,et al.  Bioinspired exosome-mimetic nanovesicles for targeted delivery of chemotherapeutics to malignant tumors. , 2013, ACS nano.

[34]  M. Wood,et al.  Exosomes for targeted siRNA delivery across biological barriers. , 2013, Advanced drug delivery reviews.

[35]  G. Beatty,et al.  Harnessing the antitumor potential of macrophages for cancer immunotherapy , 2013, Oncoimmunology.

[36]  Meg Duroux,et al.  A comprehensive overview of exosomes as drug delivery vehicles - endogenous nanocarriers for targeted cancer therapy. , 2014, Biochimica et biophysica acta.

[37]  Tianzhi Yang,et al.  Exosome Delivered Anticancer Drugs Across the Blood-Brain Barrier for Brain Cancer Therapy in Danio Rerio , 2014, Pharmaceutical Research.

[38]  R. Jenkins,et al.  Effective intravenous therapy for neurodegenerative disease with a therapeutic enzyme and a peptide that mediates delivery to the brain. , 2014, Molecular therapy : the journal of the American Society of Gene Therapy.

[39]  Richa Gupta,et al.  GDNF-Transfected Macrophages Produce Potent Neuroprotective Effects in Parkinson's Disease Mouse Model , 2014, PloS one.

[40]  Jian Song,et al.  A doxorubicin delivery platform using engineered natural membrane vesicle exosomes for targeted tumor therapy. , 2014, Biomaterials.

[41]  Samuel A Wickline,et al.  Maximizing exosome colloidal stability following electroporation. , 2014, Analytical biochemistry.

[42]  A. Ashton,et al.  Exosomes: Mechanisms of Uptake , 2015, Journal of circulating biomarkers.

[43]  Richa Gupta,et al.  Exosomes as drug delivery vehicles for Parkinson's disease therapy. , 2015, Journal of controlled release : official journal of the Controlled Release Society.

[44]  Megan E Bosch,et al.  Neuroinflammatory paradigms in lysosomal storage diseases , 2015, Front. Neurosci..

[45]  Myung Soo Kim,et al.  Development of exosome-encapsulated paclitaxel to overcome MDR in cancer cells. , 2016, Nanomedicine : nanotechnology, biology, and medicine.

[46]  Lauren E. Gillespie,et al.  Intracerebroventricular gene therapy that delays neurological disease progression is associated with selective preservation of retinal ganglion cells in a canine model of CLN2 disease , 2016, Experimental eye research.

[47]  Alexander V Kabanov,et al.  Macrophage exosomes as natural nanocarriers for protein delivery to inflamed brain. , 2017, Biomaterials.

[48]  Xue-Qing Zhang,et al.  Drug Delivery to the Brain across the Blood-Brain Barrier Using Nanomaterials. , 2017, Small.

[49]  Yoosoo Yang,et al.  Exosome-SIRPα, a CD47 blockade increases cancer cell phagocytosis. , 2017, Biomaterials.

[50]  Myung Soo Kim,et al.  Engineering macrophage-derived exosomes for targeted paclitaxel delivery to pulmonary metastases: in vitro and in vivo evaluations. , 2018, Nanomedicine : nanotechnology, biology, and medicine.