Exosomes, Extracellular Vesicles A Technology Review

Transcription

1 Exosomes, Extracellular Vesicles A Technology Review 1

2 Author, Data Collection Date, Notes The Author Gary M. Oosta, holds a Ph.D. in Biophysics from Massachusetts Institute of Technology and a B.A. in Chemistry from E. Mich. Univ. He has 25 years of industrial research experience in various technology areas including medical diagnostics, thin-layer coating, bio-effects of electromagnetic radiation, and blood coagulation. Dr. Oosta has authored more than 20 technical publications and is an inventor on 77 patents worldwide. In addition, he has managed research groups that were responsible for many other patented innovations. Dr. Oosta has a long-standing interest in using patents and publications as strategic technology indicators for future technology selection and new product development. info@selectbio.com Data for this report was collected on March 7, Annual values for 2018 were extrapolated from data. Four year CAGR s used data from 2014 and This presentation is not management, legal or accounting advice. While we believe that the results were accurate at the time of publication, the results are provided without warranty. Select Biosciences All rights reserved. 2

3 Exosomes, Extracellular Vesicles & Other Particles: Topic Introduction & the Analysis Process Summary 3

4 Exosomes, Extracellular Vesicles: Topic Introduction Using keywords to cast technical publications into market focuses, products, product features, materials, processes and methods provides a uniquely accurate picture of how the technology is developing. Such a technological picture also contains unique insights into the structure of the market itself. The focus of this report is on Exosomes, extracellular vesicles and other bodies that may contain information from a cell. Our report presents a snapshot of field that we believe is changing focus. We frame the data in the context of the current state of Exosomes and ECV s To prepare our report, we utilized a four step process. 1. We IDENTIFIED technical trends in a broadly selected literature database by categorizing and segmenting the database into products, product features, materials, processes and methods to form a model. 2. We MEASURED each trend progress with unique yardsticks. 3. We VISUALIZED the trends so that you can see them for yourself. 4. We PRESENTED our conclusions concisely. In this report, we analyzed 47,643 publications which en bloc represent the entire body of literature of the Exosome and ECV space. By casting the technical literature into technology segments, disease-related segments and market-related segments, we believe that we can create an unbiased view across the landscape as a means to identify market segments, trends, and important niches. 4

5 Exosomes & EVs are a rapidly expanding area. The Exosome space as represented by our database of 47,643 PubMed titles and abstracts is a rapidly expanding area.. From 2014 to 2017, the CAGR was 9.3%, a significant growth rate even in biotech. We use this value (9.3%) as a benchmark to judge whether a specific segments is growing faster, slower or at the norm for the database. Comprehensive Study Database 5

6 Journals in the Exosome, ECV Database The Database contains 3733 journals, and the expected journals top the list. One way to validate the utility of the database is to be sure that it contains journals that cover the Exosome & ECV area. The validation is by experience in the area. Rank Journal Number of Papers Rank Journal Number of Papers Rank Journal Number of Papers Rank Journal 1 J. BIOL. CHEM J. NEUROCHEM EUR. J. IMMUNOL J. CLIN. INVEST PLOS ONE BIOCHEMISTRY METH. ENZYMOL FEBS J J. CELL BIOL NAT COMMUN SCIENCE J. CELL. MOL. MED PROC. NATL. ACAD. SCI. U.S.A CELL TISSUE RES J. THROMB. HAEMOST J. EXP. MED J. CELL. SCI J EXTRACELL VESICLES AM. J. PATHOL J. GEN. VIROL MOL. BIOL. CELL NATURE BIOCONJUG. CHEM BIOPHYS. J TRAFFIC THROMB. HAEMOST NUCLEIC ACIDS RES J. LEUKOC. BIOL J. VIROL J. CELL. PHYSIOL MOL. PHARM TRENDS CELL BIOL BIOCHIM. BIOPHYS. ACTA CANCER RES J. CELL. BIOCHEM CELL REP SCI REP CURR. BIOL ACS NANO J. HISTOCHEM. CYTOCHEM J. IMMUNOL INFECT. IMMUN CIRC. RES ONCOL. REP BIOCHEM. BIOPHYS. RES. COMMUN PLOS PATHOG NEUROSCIENCE SEMIN. CELL DEV. BIOL METHODS MOL. BIOL MOL. CELL. BIOL ENDOCRINOLOGY VACCINE J. NEUROSCI VIROLOGY HUM. MOL. GENET CANCER LETT ONCOTARGET NAT. CELL BIOL INT J PHARM PROTEOMICS BIOCHEM. J AUTOPHAGY ONCOGENE DEV. BIOL EXP. CELL RES AM. J. PHYSIOL CELL. MOL. LIFE SCI AM. J. PHYSIOL. RENAL PHYSIOL EMBO J INT J MOL SCI DEVELOPMENT ANTICANCER RES BLOOD ADV. EXP. MED. BIOL MOL. CELL APOPTOSIS J CONTROL RELEASE BRAIN RES AM. J. PHYSIOL., CELL PHYSIOL ANN. N. Y. ACAD. SCI BIOMATERIALS CELL. MICROBIOL INT. J. CANCER J. LIPID RES CELL FASEB J ARTERIOSCLER. THROMB. VASC. BIOL BIOL. REPROD EUR. J. CELL BIOL BIOCHEM. SOC. TRANS CURR. OPIN. CELL BIOL TRANSFUSION FEBS LETT DEV. CELL HEPATOLOGY BIOCHEM. PHARMACOL THROMB. RES FRONT IMMUNOL J. PHYSIOL. (LOND.) KIDNEY INT. 78 There were 3581 unique journal titles in our database. Number of Papers 6

7 Regions in the Exosomes & ECV Database PubMed provides address information for each author. Addresses can be mined to identify the location (country and region of the world) where the work is being done. Clearly, the US, Asia and Europe are the dominant areas, and each one contributes a similar number of author locations. The same analysis can also be done by country. Region Percent of Total EUROPE 36.2% USA-COUNTRY 28.8% ASIA 27.1% NORTH AMERICA 3.3% AUSTRALIA 2.6% CENTRAL, SOUTH AMERICA 1.3% AFRICA 0.52% MIDDLE EAST 0.15% CARIBBEAN % POLYNESIA, OCEANIA % 7

8 Exosome-Related Terms We extracted and counted the terms related to exosomes by year. From that data, we calculated 4-year CAGR s and plotted the temporal tends. Green indicates that the area is contracting. Red indicates growth. The terms extracellular vesicle, exosome and nanovesicle show strong growth. Exosome-Related Terms 4-Yr CAGR CELL-DERIVED MICROPARTICLE -4.62% CIRCULATING MICROPARTICLE 0.00% APOPTOTIC BODY_ APOTOTIC BLEB 2.20% CELL-DERIVED MICROPARTICLE -4.62% CELL-DERIVED VESICLE OR PARTICLE OR MICROPARTICLE 8.93% ECTOSOME_ ECTOSOMES 18.92% ENDOSOME, (S), (AL), (IC, -X -1.67% EXOSOME, (S), (AL), -X 25.28% LYSOSOME 3.20% AUTOPHAGOSOME 10.14% ENDOLYSOSOME -8.34% LIPOSOME 12.91% LYSOSOME 1.97% PHAGOSOME 5.74% EXTRACELLULAR VESICLE 42.35% MULTIVESICULAR BODIES (MVBs) % SECRETORY VESICLES (FROM GOLGI) 5.38% SYNAPTIC VESICLES -6.60% MICROVESICLE 15.62% NANOVESICLE 22.81% PLATELET_DERIVED MICROPARTICLE 2.20% 8

9 Trends in Main Exosome-Related Terms The 4-year CAGR s indicated which areas are showing current growth. Temporal plots of authors uses of exosomerelated terms area similarly instructive. These are the MAIN terms. Notice that many terms are nearly buried in the noise at the bottom of the char.t 9

10 Trends in Smaller Exosome-Related Terms The 4-year CAGR s indicated which areas are showing current growth. Temporal plots of authors uses of exosomerelated terms area similarly instructive. These are the SMALLER terms. Notice that many terms are nearly buried in the noise at the bottom of the char.t 10

11 Sample Types in the DB Plasma, blood and serum ae the dominant sample types in the Exosome database. Urine (blue) is emerging as is biofluid (brown). Many samples types appear to unexplored. 11

12 Larger Common Technologies Common technology methods support developments in Exosomes and ECV s. CAGR s range from 6% to 25+% fluorescence antibody western blot spectrometry mass spec ultra-centrifuge centrifuge chromatography 12

13 Smaller Technologies Supporting Exosome & EVs Many smaller sized but common technologies are being used in Exosome and ECV developments. Notice Scale Change Precipitation AFM manufacturing Density gradient centrifugation 13

14 Imaging Methods in Exosomes & EVs The general terms in imaging are the most common. 14

15 Liquid Biopsy: A Newer Assay Term While traditional assay methods are growing in the exosome & ECV area, the idea of a liquid biopsy is exploding onto the scene. 15

16 Stem Cells in Exosomes The keywords stem cells and mesenchymal stem cells are most important in exosome research with 4-yr CAGR s of 30% and 37%, respectively. Other stem cell types are mentioned less frequently, but the trend in nearly all cases is upward. 16

17 Cell Signaling: Large Area in Exosomes Cell signaling is a large, active area in exosome research. The keyword signaling pathway is a specific growth area. Other themes that we track remain fairly small. 17

18 Communication: An Exosome Function Exosomes are thought to participate in cell-to-cell communication. The research agenda is described in the table of adjacent words. Communication Keyword % Total INTERCELLULAR COMMUNICATION 750 CELL-TO-CELL COMMUNICATION 285 CELL-CELL COMMUNICATION 182 CELL COMMUNICATION 80 CELLULAR COMMUNICATION 61 MEDIATE INTERCELLULAR COMMUNICATION 60 INTERCELLULAR COMMUNICATIONS 46 VESICLES INTERCELLULAR COMMUNICATION 22 EXOSOME-MEDIATED INTERCELLULAR COMMUNICATION 21 INTRACELLULAR COMMUNICATION 16 MEDIATE CELL-CELL COMMUNICATION 15 JUNCTIONAL INTERCELLULAR COMMUNICATION 15 INTER-CELLULAR COMMUNICATION 14 CELLΓÇôCELL COMMUNICATION 12 MEDIATE COMMUNICATION 12 EXOSOMES INTERCELLULAR COMMUNICATION 11 FACILITATE INTERCELLULAR COMMUNICATION 11 CELL-CELL COMMUNICATIONS 10 MEDIATE CELL-TO-CELL COMMUNICATION 10 NEURONAL COMMUNICATION 10 CELLULAR COMMUNICATIONS 9 MEDIATING INTERCELLULAR COMMUNICATION 9 EXTRACELLULAR COMMUNICATION 8 INCLUDING INTERCELLULAR COMMUNICATION 8 JUNCTION INTERCELLULAR COMMUNICATION 8 EXTRACELLULAR RNA COMMUNICATION 8 18

19 Interactions in Exosomes Interactions is a key theme in exosome research. The table shows the most frequent 30 words modifying the word interaction (of more than 3300 separate, non-trivial keyword pairs) in our exosome database. 1. DIRECT INTERACTION 2. PROTEIN-PROTEIN INTERACTION 3. ELECTROSTATIC INTERACTION 4. SPECIFIC INTERACTION 5. CELL-CELL INTERACTION 6. CELLULAR INTERACTION 7. PROTEIN INTERACTION 8. PHYSICAL INTERACTION 9. MOLECULAR INTERACTION 10. FUNCTIONAL INTERACTION 11. HOST-PATHOGEN INTERACTION 12. MEMBRANE INTERACTION 13. HYDROPHOBIC INTERACTION 14. COMPLEX INTERACTION 15. GENETIC INTERACTION 16. DYNAMIC INTERACTION 17. CELL INTERACTION 18. POTENTIAL INTERACTION 19. CELL-MATRIX INTERACTION 20. RECEPTOR INTERACTION 21. IONIC INTERACTION 22. LIGAND-RECEPTOR INTERACTION 23. TRANSIENT INTERACTION 24. STRONG INTERACTION 25. LIPID INTERACTION 26. INTRAMOLECULAR INTERACTION 27. PROTEIN-LIPID INTERACTION 28. HIGH AFFINITY INTERACTION 29. MEDIATE INTERACTION 30. RECEPTOR-LIGAND INTERACTION 19

20 Biomarkers: Rapidly Growing in Exosomes Biomarkers are a significant theme in exosome, ECV research and has a 4-yr CAGR of 30%. 20

21 MicroRNAs Associated with Exosomes, EVs: 1 Naming in micrornas is fairly standard. We extracted and standardized MIR names from our exosome database and associated the MIR names with selected particle types. We sorted the data by the frequency of association with exosomes. The frequency suggests strong connection to cancer research for exosomes and extracellular vesicles, but not for the other particles examined. This may be a true finding or it might be driven by our selection of main search strategies. Page 1 Results are presented in descending order of the number of papers in common for exosomes and MIR. In total there were 354 MIR names found. MicroRNA CELL-DERIVED EXTRACELLULAR ENDOSOME EXOSOME LYSOSOME MICROPARTICLE VESICLE MicroRNA CELL-DERIVED MICROPARTICLE ENDOSOME EXOSOME EXTRACELLULAR VESICLE LYSOSOME MIR MIR MIR MIR MIR MIR LET MIR MIR MIR MIR MIR MIR MIR MIR MIR MIR MIR MIR MIR MIR MIR MIR MIR MIR MIR MIR MIR MIR MIR MIR MIR MIR MIR MIR MIR MIR MIR MIR MIR MIR MIR MIR MIR MIR MIR MIR MIR MIR MIR MIR MIR MIR MIR MIR MIR MIR MIR MIR MIR

22 MicroRNAs Associated with Exosomes, EVs: 2 Naming in micrornas is fairly standard. We extracted and standardized MIR names from our exosome database and associated the MIR names with selected particle types. We sorted the data by the frequency of association with exosomes. The frequency suggests strong connection to cancer research for exosomes and extracellular vesicles, but not for the other particles examined. This may be a true finding or it might be driven by our selection of main search strategies. Page 2 Results are presented in descending order of the number of papers in common for exosomes and MIR. In total there were 354 MIR names found. MicroRNA CELL-DERIVED MICROPARTICLE ENDOSOME EXOSOME EXTRACELLULAR VESICLE LYSOSOME MicroRNA CELL-DERIVED MICROPARTICLE ENDOSOME EXOSOME EXTRACELLULAR VESICLE LYSOSOME MIR MIR MIR MIR MIR MIR MIR MIR MIR MIR MIR MIR MIR MIR MIR MIR MIR MIR MIR MIR MIR MIR LET-7G MIR MIR MIR MIR MIR MIR MIR MIR MIR MIR MIR MIR MIR MIR MIR MIR MIR MIR MIR LET-7F MIR LET-7I MIR-378I MIR MIR MIR MIR MIR MIR MIR MIR MIR MIR MIR MIR MIR MIR

23 Few Clinical Trials in Exosomes, EVs so far As Exosomes and ECV s move from research to treatment in the clinic, more clinical trials can be expected. The growth of the clinical trial keyword (blue triangles, 4-Yr CAGR of 26%) and the relatively small numbers of papers talking of specific clinical trial phases indicates that the process is still in its infancy. Diagnostic applications probably would not take the clinical trials path and are probably not represented in this chart. 23

24 Cancer in the Exosome Database Cancer is a large and persistent theme in Exosomes. With a 4-year CAGR of 13%, cancer is a research focus and a driver of exosome publications growth. 24

25 Cancer Types in Exosomes and EVs Cancer is an old and growing theme in the Exosomes or ECV s area. Breast cancer is the largest of the areas studied and has a growth rate of 7.8% (4-yr CAGR). Skin cancer (next largest) has a CAGR of 17%. 25

26 Cardiovascular Themes in Exosomes The themes cardiovascular and cardiovascular disease are growth areas in exosome research with 4-yr CAGRS of 15% each. Myocardial Infarction is a keyword with at 39% 4-yr CAGR. Stroke is also a growth area. 26

27 Summary The Process. To identify trends in exosome research, we assembled a comprehensive database of 47,643 publications using multiple, overlapping search strategies. This data set provides a comprehensive, worldwide view of exosome research, and a data set that can be efficiently mined to provide an unbiased view of research trends as they actually exist. Exosomes is a rapidly expanding area with a growth rate that is almost exponential. The overall 4-year CAGR for exosomes is 9.3%, an indicator of an area experiencing explosive growth. We use this CAGR as a benchmark. If a sub-trend has a CAGR above 9.3%, we mark that trend as a growth driver. Exosome research is a worldwide enterprise. Most work is concentrated in Europe, the US, and Asia (primarily in China and Japan). The vocabulary in Exosomes and Extracellular Vesicles is complex. In our comprehensive database, we extracted 1483 variations of an -osome name, 10,461 types of particles (two to three words) and 30,665 names for vesicles (also two to three words). However, the words exosome, endosome and extracellular vesicle are most common now. Using the database and Python s natural language tool kit, we can parse each title and abstract into parts of speech remarkably accurately. By looking at the nouns and the 4-year CAGR for each noun we can identify those words that have exceptional growth rates. Applying a size metric as well allows us to find those areas (described by that noun) that most strongly influence growth in exosome research. We track 31,902 pre-defined segments in our research. Using our past experience, we define a segment as keyword(s) describing biomarkers, genes, materials, processes, technologies, and products or product features. We found 6990 of our pre-defined segments in the exosome database. Analysis of these trends also provides insights into growth areas in exosomes. 27