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Molecular Diagnostics
Exosomes contain not only protein as once thought, but also different types of RNA transcripts, such as messenger RNA (mRNA), microRNA (miRNA), other noncoding RNA, ribosomal RNA (rRNA), and transfer RNA (tRNA). These differences in exosome-derived RNA profiles could be harnessed to distinguish healthy vs. disease states. The focus has been on developing noninvasive, highly specific biomarkers based on the RNA content of exosomes.
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There are several potential advantages to the use of exosomes in molecular diagnostics. Because exosomes contain nucleic acid information from their cell of origin, genetic information about cells in the body can be achieved without direct access to those actual cells. The ability to detect the nucleic acid profile of a tumor for example, in a noninvasive way, via a blood draw or urine sample, without the need for a potentially invasive tissue biopsy is a significant advance, especially when sample tissue is difficult to access. Since exosomes can be collected in a straightforward way and with regularity, real-time tracking of a patients disease progression is possible. Prostate cancer is a good example of how exosomes could improve patient management. It is estimated that 30% of men age 50 or older will have some form of prostate cancer (although only about 15% of men will be diagnosed during his lifetime); however, many of these men have low-risk prostate cancer that will not likely progress to a life-threatening stage. Currently, diagnosis of prostate cancer involves a screening test that measures the concentration of prostate specific antigen (PSA) in the blood. Elevated levels of PSA could indicate a prostate cancer diagnosis; however, a PSA test alone is not enough and patients also require a biopsy for diagnosis. Unfortunately, a majority of prostate biopsies do not indicate aggressive disease. These biopsies have significant morbidity: They are painful, costly, and infection is a significant risk. A diagnostic that could aid the decision to biopsy could help patients and physicians. Exosomes from prostate cancer cells can be obtained from a simple urine sample, making an exosome-based test essentially noninvasive. Exosome tests may able to detect several RNAs that code for key biomarkers in prostate cancer, such as PCA-3 and TMPRSS2:ERG. Other tumor markers can be added as they are identified to develop a patients exosomal RNA profile. By looking at many relevant markers its hoped that accuracy of diagnosis will be improved and result in better decision making regarding the need for biopsy. Initial clinical studies have shown exosome tests for prostate cancer have a 70% accuracy rate, which is almost comparable to the accuracy of a biopsy. Implementation of these tests, and/or use in conjunction with the standard PSA test could be a huge improvement to the diagnosis and prognosis of a very difficult disease.
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Another condition where exosomes have the potential to change the game from a diagnostic and therapeutic development standpoint is slowly emerging diseases in which clinical manifestation occurs when the disease is quite advanced. Several neurodegenerative diseases, such as Alzheimers disease and Parkinsons disease, fit this profile. Both have been extremely challenging for the pharmaceutical industry and drugs that are available today are at best palliative rather than disease modifying. The identification of Alzheimers disease-associated biomarkers has been a challenge because brain biopsies are not feasible. An exosome-based test could potentially help identify useful markers because brain cells release exosomes into the CSF. In addition, a property of exosomes that can be exploited for this use is their long-term stability under standard storage conditions. Exosomes containing RNA molecules collected from biofluids are stable under various storage conditions, such as freezing, for up to several years. Biofluid biobanks obtained from previous clinical studies or studies that follow subjects longitudinally for many years could be used as sources to identify possible biomarkers retrospectively. Some of these patients eventually developed Alzheimers, so samples from individual patients that span their entire disease progression are already available for testing.
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Challenges
The most significant challenge to working with exosomes involves their isolation and purification, not only from other biofluid components but from exosomes that are not of interest. In order for exosomes to be a reliable source of diagnostic and scientific information a robust platform to isolate exosomes of interest from the total population of exosomes, as well as removal of unwanted cellular debris, must be standardized. Such work is ongoing today. Work to further reveal the basic physiologic roles of exosomes in living organisms is also imperative if exosomes are to be used to their fullest advantage diagnostically and therapeutically. There are many questions that currently remain. What is the half-life of an exosome in the body? Which cells take up exosomes? How are the exosomes taken into cells? These are just a few of the questions that need to be answered going forward.
Summary
Exosomes are not a recent discovery. However, their potential as diagnostic, research, and therapeutic tool is new. Exosomes have the potential to significantly impact how physicians diagnose, treat, and monitor their patients in real time. The personalized nature of their information content should enable physicians to make better and more informed medical decisions. For patients, the minimally invasive nature of exosome collection should reduce morbidity of diagnostic procedures and may prevent unnecessary interventions, as with prostate cancer, as well. We expect this field to continue to evolve at a rapid pace. For more on exosomes, b e sure to check out two articles from our March 15 issue: GEN Roundup on Exosomes and Surveying the Exosome Market Landscape.
<p> Johan Skog, Ph.D. (<a href="mailto:johan@exosomedx.com">johan@exosomedx.com</a>, Phone: 646843-4944), is CSO of <a href="http://www.exosomedx.com" target="_blank">Exosome Diagnostics</a>.</p> <p> References:<br /> <sup>1</sup> <a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3155154/" target="_blank">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3155154/</a></p> <p> To enjoy more articles like this from GEN, <a href="http://www.genengnews.com/subscriptions" target="_blank">click here to
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