Exosomes can be thought of as tiny packages of potential. Given their intricate construction, exosomes may possess a much more powerful influence on the physiology of the cells they encounter than other solitary mediators, such as hormones, lipids, or cytokines.
Exosomes can be thought of as tiny packages of potential. Given their intricate construction, exosomes may possess a much more powerful influence on the physiology of the cells they encounter than other solitary mediators, such as hormones, lipids, or cytokines. Exosomes carry unique combinations of receptors and proper counter-ligands on their surface, which researchers suggest, is what enables them to target specific cell types. Because exosomes are enriched with surface antigens, they are capable of initiating multiple signaling pathways inside target cells [1]. Moreover, its cargo of nucleic acid has been shown to have a profound influence on recipient cells. The fragments of RNA ejected by cells are a type of molecular fingerprint that can provide critical clues as to what type of cancer a patient has. Furthermore, since the export of RNA from the nucleus is delayed until processing is completed, it is also possible to shudown RNA splicing thus blocking RNA from exiting the nucleus. This forms the basis for regulating the transport of mRNA in clinical applications, and has allowed researchers to block the uptake and spread of the HIV virus, the virus that causes AIDS [2].
Image taken from Frontiers in Science, www.frontiersin.org
Exosome-Based Commercialization Over the past decade, the development of large-scale protein analysis techniques has allowed researchers to begin categorizing the composition of exosomes for the first time. Proteomic analysis was first performed on the exosomes of dendritic cells, and has steadily moved outward from there. The entire collection of known exosomal molecules can be found in the ExoCarta compendium [3]. Interest in exosomes has steadily grown when research showed their potential to treat disease, produce new types of vaccines, and detect disease. Many companies have taken the message to heart and are developing new diagnostic and therapeutic applications. We will highlight some of the recent news in the field surrounding exosome research. Diagnostics New diagnostic arrays that can examine exRNA in detail are being highly praised as new "value added" applications capable of identifying potential biomarkers of disease. Next-generation sequencing of exRNA is currently being applied to identify potential biomarkers, as highlighted in a recent report by Kurochkin and co-workers titled, "Who Sequenced exRNA from Breast Cancer Cell Lines?". Their data revealed that, "exosomal transcripts are representative of their cells of origin and thus could form the basis for detection of tumor-specific markers." Among the traditional methods for exRNA analysis, qPCR and various other library preparations for next-generation sequencing platforms are now available, such as those being offered from Life Technologies for Ion Torrent sequencing. Exosome Diagnostics, is developing a biofluid-based molecular diagnostic tests to be used in personalized medicine, recently announced they will use Applied Biosystems qPCR platform for its biofluid in vitro diagnostics oncology. Their plans call for multi-center clinical trials in brain cancer and prostate cancer. In July 2013, Exosome Diagnostics announced a partnership with Qiagen, to develop and commercialize high-performance exosome diagnostic co-branded kits, for the capture and processing of the microRNA (and DNA) fragments from biofluid exosomes and other MVs. Caris Life Sciences, is another company focused on personalized medicine. Through state-of-the-art lab testing, including tumor profiling and innovative blood-based cancer diagnostics, they have created what it calls Carisome® Microvesicle Technology. Each population of circulating microvesicle (cMV; e.g. exosomes, apoptotic cells, microparticles) express an array of proteins that reflects its cell-of-origin. This technology system has the capacity to identify and qualify circulating MVs launched in the blood that function as a signaling device for various types of cancer. Caris utilizes both DNA- and antibody-based assays in order to obtain cMV "biosignatures" that have been correlated with colorectal, prostate, breast, and lung cancer, as explained here in various posters, papers, and abstracts.
Image taken from www.carislifesciences.com
In other diagnostic news, Genome Web declared that Aethlon Medical (see below) established its fully-owned subsidiary company, Exosome Sciences, to "pursue exosome-established strategies" for diagnosing and tracking the progression of cancer, communicable diseases, as well as other disorders. Their facility in Langhorne, Pennsylvania is a CLIA-licensed laboratory where much of their work on exosomes will likely take place. Aethlon said it will contribute diagnostic-related technology to Exosome Sciences, including the "Enzyme Linked Lectin Specific Assay," which has been validated to identify the presence of exosomes underlying HIV, tuberculosis, and cancers such as ovarian, melanoma, breast, lymphoma, and colorectal. Therapeutics Therapeutic strategies related to exosomes are grouped into two broad categories: targeted delivery of therapeutic agents and the interruption of exosome-mediated diseases, such as HIV. A review published by Marcus & Leonard printed earlier this year in Pharmaceuticals (Basel) is wittily titled: FedExosomes: Engineering Therapeutic Biological Nanoparticles that Truly Deliver. Their report summarizes the current gains in harnessing exosomes for gene therapy. They also talk about the possibility to engineer exosomes that could ship RNA more efficiently and establish technology platforms that are more robust. In a widely cited article by Stephen J. Gould titled, "The Trojan Exosome Hypothesis," it was proposed that exosome exchange is exploited by retroviruses in order to generate copies of retroviruses as a low-efficiency, but mechanistically effective means of infection. They state that retroviruses pose an unsolvable paradox for adaptive immune responses, that retroviral antigen vaccines are unlikely to provide prophylactic protection, and that alloimmunity is a central component of antiretroviral immunity." Finally, the Trojan exosome hypothesis has important implications for the fight against HIV and AIDS, including how to develop new antiretroviral therapies, assess the risk of retroviral infection, and generate effective antiretroviral vaccines. [4] Exosomes have also found a purpose when it comes to fighting malaria, as well. Scientists in Melbourne found that malaria parasites "talk" to one another, a social behavior he cites as a way to ensure the parasite's chances for survival. In one account, published in BioQuick News, author Michael D. O'Neill suggests that these findings, "could provide a niche for developing antimalarial drugs and vaccines that prevent or treat the disease by cutting these communication networks. With regard to actual exosome products currently available on the market, Aethlon Medical here in San Diego has developed the Aethlon Hemopurifier®, a medical device that captures exosomes released by various cancers, including breast and colon cancer, lymphoma, melanoma, and ovarian cancer. In collaboration with the Sarcoma Oncology Center based in Santa Monica, Aethlon is studying the ex vivo effectiveness of its Hemopurifier® to clarify immunosuppressive exosomes from the blood of advanced-stage cancer patients. The study is evaluating twenty-five patients, including five with metastatic cancer of the following types; non-small cell lung cancer, prostate cancer, melanoma, head and neck cancer, and sarcoma [5].
The Aethlon Hemopurifier® (courtesy of aethlonmedical.com)
Another medical device, HER2osome, provides a therapeutic strategy to maximize the ability of the immune system and established drug therapies to combat HER2+ breast cancer, which is characterized by aggressive growth and poor prognosis resulting from the over-expression of HER2 protein. HER2osome is a novel medical device, whose goal is to inhibit HER2+ breast cancer progression by reducing the circulatory presence of HER2 protein and tumor-secreted exosomes that contribute to the development and progression of breast cancer. Research publications indicate that breast cancer exosomes suppress the immune response, stimulate angiogenesis, contribute to the spread of metastasis, and inhibit the therapeutic benefit of Herceptin® (trastuzumab), a leading monoclonal antibody treatment against the HER2+ breast cancer. As an adjunct therapeutic candidate, HER2osome offers to fill an unmet medical need and enhance the benefit of Herceptin® and standard of care chemotherapies without adding drug toxicity or interaction risks [6]. SOURCES [1] Keller, S., et al, Exosomes: From biogenesis and secretion to biological function, Immunology Letters 107 (2006) 102108. [2] Molecular Biology of the Cell. by John Wilson, Tim Hunt; Garland Science, 4th edition, 2002. Page 442. [3] Mathivanan S., Simpson RJ: ExoCarta: A compendium of exosomal proteins and RNA. Proteomics. 2009, 9:49975000. [4] Gould S., Booth A., Hildreth J. Trojan Exosome Hypothesis. The National Academy of the Sciences. Vol. 100, No. 19. 2003. <http://www.pnas.org/content/100/19/10592.short>. [5] Aethlon Hemopurifier®. Aethlon Medical. <http://www.aethlonmedical.com/products/hemopurifier/index.htm> [Sept. 28, 2014]. [6] Aethlon HER2osomeâ„¢. Aethlon Medical. <http://www.aethlonmedical.com/products/her2osome.htm> [Sept. 28, 2014]. Parts of this article was sourced from zon.trilinkbiotech.com