The Potential of Exosomes
Exosomes are moving toward clinical use in numerous and diverse ways
There are around 37 trillion cells in a human body—and like any collective of diverse individuals they rely upon constant communication to work together. Just over a decade ago a research team in Sweden published in Nature Cell Biology a remarkable new mechanism that allows our cells to communicate.1
If cells failed to converse, it would be impossible for them to arrange themselves into a creature as simple as an earthworm, let alone a structure as highly complex as the human brain.
Cells in difficulty, such as heart muscle cells after a heart attack, would be unable to call for help. And the many cell types that make up our immune system would not be able to coordinate to fight off infections.
But it turns out cell to cell communication is ever more complex and sophisticated than ever thought. Cells don’t just send each other status updates, the Swedish researchers showed. Cells exchange genetic code directives: sections of ribonucleic acid (RNA), wrapped inside and on nano-sized packages called exosomes.
The recipient cells that took up these snippets of genetic instruction were reprogrammed in response—making exosomes a critical link for cell, tissue and organ function.
This 2007 seed of discovery fell on fertile ground. The realisation these exosomes, little packets of proteins, RNA and other biomolecules (once dismissed as cellular garbage), are actually a vital component of cell to cell communication spurred rapidly expanding research activity, mainly to address a diverse range of critical, unmet medical needs.
During 2008, the year following this pivotal exosome discovery, just over 1000 exosome-related research papers were published, according to Google’s count.
One decade later, during 2018, over 11,000 exosome papers appeared. The growth of biotech firms driving exosomes’ transition from academic curiosities into clinical use has been similarly spectacular.
The little seed of discovery has become a vast branching tree of applications – and the more we discover about exosome behaviour, the more new offshoots of exosome research appear. Today, the major branches of exosome research cover medical diagnosis (diagnostics), regenerative medicine, and therapeutics delivery.
Every cell type in the body releases exosomes. They are found in every biofluid, including milk, blood, urine, semen and saliva.
As the content of each exosome depends upon the cell type that released it, and the status of that cell at the time of its release, exosomes potentially offer a detailed readout of the current health of every tissue in the body – simply by taking a blood, saliva or urine sample.
By learning to decipher the messages that circulatory exosomes carry, we could potentially identify diseases or medical problems long before any outward symptoms occur and without needing to do invasive surgery. For many conditions, early diagnosis makes all the difference for successful treatment.
Concussions on the sports field, the battlefield, or following an accident such as a car crash, require fast, accurate diagnosis.
It has recently been discovered that repeated head knocks increase the risk of developing neurodegenerative disorders including Alzheimer’s and chronic traumatic encephalopathy later in life. As the brain seems particularly vulnerable if it receives two blows in close succession, quick and accurate concussion diagnosis is vital to minimise long term risk.
The long-term effects of head trauma seem to relate to the temporary disruption of a protective structure called the blood-brain barrier (BBB), which usually keeps the brain sealed off from the rest of the body.
BBB disruption allows potentially damaging biomolecules into the brain – but also lets brain biomolecules out. Detecting brain cell exosomes in the bloodstream can be a quick way to diagnose concussion.2 Monitoring brain exosome levels in the blood in the days and weeks after a head trauma—or longer—can also be used to track recovery.3
Exosomes’ diagnostic potential begins before a baby has even left the womb.
During pregnancy, exosomes continually pass back and forth between maternal and foetal cells—for instance, it is how the foetus signals that its organs have fully developed, triggering the mother to go into labour. From blood samples taken from the mother, researchers can potentially monitor foetal health and growth.4
Exosomes isolated from blood samples taken from women in the first trimester of pregnancy could potentially be used as early predictors of gestational hypertension, preeclampsia and foetal growth restriction.5
Exosomes swabbed from the mouth of pregnant women during the first trimester of pregnancy can give an early warning of patients at risk of developing gestational diabetes before symptoms occur, a related study showed.
Exosomes also have unrivalled potential to give early warning of the diseases that catch up with us later in life.
Alzheimer’s disease, for example, can currently only definitively be diagnosed using a specialised brain scan, which is too expensive for widespread clinical use. Exosomes circulating in the bloodstream, containing the amyloid-beta protein implicated in Alzheimer’s patient brain degeneration, could become the basis of a simple blood test for early detection of the disease.6
Early intervention, before extensive damage to the brain, has already occurred and the symptoms of memory loss and personality change begin to appear, is the current target of much Alzheimer’s research.
Prostate cancer is another condition notoriously difficult to accurately diagnose.
The current test, based on prostate-specific antigen (PSA) detection, has limited utility in discriminating aggressive tumours from low-risk tumours, leading patients to have invasive treatment they may not need.
Exosomes collected from urine samples could offer a more accurate way for doctors to detect aggressive prostate cancers.7 In June 2019, the US Food and Drug Administration granted biotech firm Bio-Techne ‘breakthrough device designation’ for their exosome-based test to detect aggressive prostate cancer biomarkers in urine samples. Breakthrough status should accelerate the review process of the new test.
As exosomes are released by virtually every cell type in the body, researchers have barely scratched the surface of exosomes’ diagnostic possibilities, but the potential is already clear.
In parallel, researchers are making great strides developing high-throughput techniques to analyse the exosomes in a biosample. Exosome-based disease diagnosis is capturing significant investor interest.
In June 2019, Thrive, a spin-out of Johns Hopkins University announced it had secured US$110 million in Series A funding to develop CancerSEEK, a blood test that uses exosomes to detect a range of cancer types at the early stage of the disease. And in August 2019, a team in Sweden published its work on an antibody-based method that can use the unique pattern of proteins on exosomes’ surface to identify the cellular source of exosomes.8
Their high-throughput approach can identify the source of single exosomes in a biological sample. The researchers launched a spin-out company to develop the technology for early cancer diagnosis.
The discovery that exosomes can reprogram recipient cells has wide-ranging implications for the way we treat disease. A major research focus has been on the exosomes released by stem cells, and the rejuvenating effect they have on recipient cells.
Stem cells are regenerative cells naturally present in the body. These progenitor stem cells have the potential to become one of the many specialised cells that make up the body, from neurons to heart cells to blood cells.
Over the last 25 years, a large number of clinical trials have been run around a presumed potential for stem cells administered to the patient to home in at sites of degeneration or damage in the body, and directly replace the dysfunctional cells.
Initial studies to test this hypothesis, in animals and humans, showed promise—but stem cell therapy has not lived up to the hype. Injecting live stem cells into patients has proven fraught with potential complications.9 And as we now know, most transplanted stem cells don’t stick around long in the recipient’s body to replace damaged cells; the majority is cleared within a week.
As researchers from Oxford University10 to Scripps11 have now concluded, it’s the exosomes that stem cells release, rather than the cells themselves, that imparts the therapeutic benefit.
Exosomes isolated from stem cells can have powerful effects in numerous health conditions.
They can reverse the breakdown of cartilage in the joints, potentially stopping osteoarthritis. They can promote the recovery of heart tissue following a heart attack. They can rein in an active immune system, potentially treating conditions ranging from multiple sclerosis to type I diabetes.
They can enhance functional recovery following a stroke. The possibilities appear to be almost endless.
So far, most research has been at the stage of animal tests, but a number of biotech companies are now transitioning rapidly into human clinical trials. Among the forerunners are Florida-based Aegle and Melbourne’s Exopharm.
There is also Cambridge, Massachusetts-based Codiak BioSciences, targeting cancer and immune system diseases; and Athens, Georgia-based ArunA Biomedical initially targeting stroke, then other central nervous system disorders and neurodegenerative diseases.
But as well as their potential to treat these specific diseases, exosomes have the potential to have body-wide regenerative effects. In our youth, our bodies rapidly repair themselves.
But as we age we accumulate damage and fall into a period of increasing ill-health. Exosomes might underpin the revolution in treating age-related diseases that a growing number of researchers are calling for: that we should target the underlying causes that seem to leave us susceptible to disease in old age.12
Exosomes have proven to play a role in body-wide health. As we age, the balance of exosomes found circulating in the body changes; the number of inflammatory exosomes rises, while the number of regenerative exosomes declines.
The whole-body health benefits of exercise also seem to be at least partly mediated by exosome release. Infusions of regenerative exosomes isolated from stem cells are one way we could restore the effective repair mechanisms we enjoy in our youth.
Exosomes’ diminutive size and the proteins they display on their surface are like a passport to travel, enable them to roam freely around the body but also have a planned destination. On reaching their target cell, they are quickly taken up before releasing their cargo directly inside the cell.
All in all, exosomes appear to be ideal vessels for delivering drugs, or other therapeutic cargo, into target cells.
For example, exosomes are being trialled to selectively deliver cancer drugs to tumour cells.
This approach maximises the amount of drug that reaches its desired target while reducing side effects by minimising the amount of drug entering healthy cells.13 Following successful animal trials—which demonstrated improved tumour penetrance and retention in tumour cells, and improved overall potency of the treatment—several human clinical trials are now underway. In what could be the ultimate trojan horse strategy, exosomes produced by cancer cells cultured in the lab could be the ideal vehicles for selectively delivering chemotherapy drugs to cancer cells in patients.14
Exosomes can even access hard-to-reach cell populations, such as the brain.
They can slip across the blood-brain barrier, a tightly sealed membrane that has added to the challenges of treating conditions such as neurodegenerative diseases. Exosomes can also cross the placental barrier, so might be used to deliver drugs against conditions such as foetal inflammation, a major cause of premature birth.
To enhance their drug delivery capabilities even further, a growing branch of exosome research is aimed at ‘engineering’ exosomes in some way. These modified exosomes may be tagged with a marker that is rapidly taken up by cancer cells or another target cell population.15
Or they may be engineered to contain genetic material to suppress cancer or correct a faulty gene.
Gene therapy holds great promise for genetic conditions such as cystic fibrosis, a disease caused by mutations in the CF transmembrane conductance regulator gene. Until now, finding vehicles to deliver gene therapy into target cells has been a stumbling block, with the virus particles and lipid particles afflicted by concerns of safety and limited efficacy.
Exosome-mediated delivery is a promising alternative option.16 And in Huntington’s disease, exosomes delivered RNA into the brain cells of mice to shut down the faulty gene responsible for the disorder, confirming RNA-loaded exosomes are promising candidates for neurodegenerative disease.17
Multiple biotech firms are now launching clinical trials to bring these ideas to people.
As a critical line of communication between our cells, exosomes play a central role in human health – and so have extraordinary potential in many areas of medicine.
From non-invasive early diagnosis of disease, to the healthspan-extending promise of exosomes from stem cells, to the engineered exosomes developed to ferry gene therapy agents to target cells, exosomes could revolutionise almost all aspects of modern healthcare.
With academic researchers expanding our understanding of exosome production and function, exosome science has strong roots and vast potential for further growth.
- Wiklander, O. B. P., et al. Science Translational Medicine 11, eaav8521 (2019)
- Ko, J. et al. Smartphone-enabled optofluidic exosome diagnostic for concussion recovery. Scientific Reports 6, 31215 (2016). https://doi.org/10.1038/srep31215
- Gill, J., et al. Higher exosomal tau, amyloid-beta 42 and IL-10 are associated with mild TBIs and chronic symptoms in military personnel. Brain Injury 32, 1359 (2018). https://doi.org/10.1080/02699052.2018.1471738
- Sheller-Miller, S., et al. American Journal of Obstetrics and Gynecology, DOI: 10.1016/j.ajog.2019.06.010 (2019)
- Hromadnikova, I. et al. International Journal of Molecular Science 20, 2972 (2019)
- Lim, C. Z. J., et al. Nature Communications 10, 1144 (2019)
- Woo, J., et al. Journal of Clinical Oncology 37, 18 (2019)
- Wu, D., et al. Nature Communications 10, 3854 (2019)
- Marks, P.W., et al. New England Journal of Medicine 376, 1007 (2017)
- Andaloussi, S. E. L., et al. Nature Reviews Drug Discovery 12, 347 (2013)
- Phinney, D. G. & Pittenger, M. F. Stem Cells 35, 851 (2017)
- Campisi, J., et al. Nature 571, 183 (2019)
- Batrakova EV, Kim MS. Wiley Interdiscip Rev Nanomed Nanobiotechnol. 8, 744-57 (2016)
- Yong, T., et al. Nature Communications 10, 3838 (2019)
- Tian, Y., et al Biomaterials 35, 2383–2390 (2014)
- Villamizar, O., et al. Molecular Therapy, DOI: 10.1016/j.ymthe.2019.07.002 (2019)
- Lee, S.-T., et al. J. Mov. Disord. 10, 45–52 (2017).
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