Exosome Therapeutic Research Emerging from the Lab
The more we study these naturally produced packets of biomolecules, the more therapeutic use they seem to lend themselves to be.
Exosomes, pro-healing nanoparticles found naturally in the body, are a new potential paradigm in healthcare that could assist in every step we take through life.
In their precarious first few days and weeks of life, premature babies often need help simply to breathe. Newborns’ very delicate lungs can be damaged by neonatal respirators and oxygen-enriched air – but exosomes could help sooth damaged airways, shifting lung cells from a pro-inflammatory to a pro-healing status, new research shows1.
At the other end of life, exosomes engineered to selectively target cells ranging from cancer cells to brain cells, look like a highly promising tool for treating age-related illnesses, and extending the number of years we can expect to stay fit, healthy and active – extending health span.
As researchers untangle the role that exosomes (also called extracellular vesicles (EVs)) naturally play in the body, the greater their therapeutic promise appears to be. “EVs represent a sweet spot between drug delivery, biologics, and cell therapies,” a multinational research team recently concluded in the journal Science Translational Medicine2. “We think EVs are likely to be the next breakthrough in medical treatment.”
Exosomes are nanoscale packets of proteins, lipids (fat molecules) and genetic material, produced and released by virtually every cell type in the body. Once thought to be merely a cellular garbage disposal system, we now know exosomes are essential for cell to cell communication.
Exosomes transfer messages and materials from cells to other cells – acting as a potent communications system that co-ordinates regeneration and repair3.
Each exosome’s content depends upon the cell that released it and the current status of that cell. The exosomes released by regenerative cells called stem cells, for example, have pro-healing anti-inflammatory effects. In many cases, the beneficial effects of stem cells seems to be almost entirely due to the exosomes they release.
As we age, the number of these beneficial exosomes in the body declines. Exosomes harvested from stem cells in the lab could top up our levels back to those we enjoyed in our youth – with myriad potential health benefits including reversing aging4. Stem cell derived exosomes are being investigated in conditions ranging from autoimmune diseases; to treating chronic kidney disease; to general wound healing; to stimulating cartilage regeneration as a treatment for arthritis5.
Stem cell are not the only potential therapeutically valuable source of exosomes. Platelets from blood produce vesicles that have been shown to treat wounds in animal studies. In other animal studies, exosomes isolated from immune cells called dendritic cells (DCs) stimulate the immune system to attack cancer cells. Current studies are examining the effect the status of the source dendritic cells has on the efficacy of exosome anticancer therapies2.
Exosomes’ role as cell-to-cell messengers, roaming freely around the body and penetrating deep into the tissues, have caught the eye of researchers working on drug delivery and drug targeting. Add in the fact the exosomes are often naturally tagged for uptake by a specific recipient cell type, and exosomes look like a natural fit for the task of delivering drugs to where they are needed in the body.
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 cells6.
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 addition to being loaded with drugs, exosomes can be further engineered to enhance their drug delivery performance. In animal studies, adding a tumour-targeting delivery tag to exosomes packed with an anticancer drug enhanced the antitumor effect while minimising side effects7.
Drugs are not the only cargo exosomes can carry. In their natural state, exosomes invariably contain RNA – snippets of genetic information that can reprogram the behaviour of the recipient cell. Exosomes therefore make ideal delivery systems for therapeutic RNA.
Hereditary genetic diseases such as cystic fibrosis, caused by specific gene mutations, could be treated using exosomes to deliver the functional version of the RNA to target cells8.
That delivery capability even extends to hard-to-reach cell populations, such as neurons in the brain.
Exosomes can slip across barricades such the blood-brain barrier (BBB) – a tightly sealed membrane that makes neurodegenerative diseases difficult to treat by conventional therapies. Animal studies show that brain diseases from Parkinson’s to Huntington’s disease could be treated with exosomes9.
In the latter case, 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 disease10.
The exosomes our cells release are status updates of the tissues the exosomes came from, broadcast to the rest of the body. Following a heart attack, for example, heart cells send out an SOS message, in the form of exosomes, calling in progenitor cells to help repair the damage11.
For people with concussion injury, exosomes in their blood that came from brain cells have been reported to indicate the severity of traumatic brain injuries12.
Deciphering the messages exosomes encode could give a detailed readout of the health status of our bodies – to potentially diagnose diseases long before any outward symptoms occur. For many conditions, early diagnosis is critical to successful treatment.
Aggressive prostate cancer has also proven difficult to 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 do not need.
Exosomes collected from urine samples appear to offer a more accurate way for doctors to detect aggressive prostate cancers13.
As an example, Exosomes could be a breakthrough in the diagnosis of Alzheimer’s disease. Alzheimer’s disease can only definitively be diagnosed in patients by 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, recent research shows14.
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.
Overcoming Prep Problems
The proliferation of promising preclinical and early stage clinical trial data using exosome-based therapies has highlighted a problem. The current standard method for isolating exosomes, using a centrifuge to separate them from cells and cellular debris, is limited by low exosome recovery yields, risk of impurities, disruption of exosome integrity. It is also slow and has limited potential for scalability.
Exopharm’s LEAP exosome isolation and purification technology overcomes this limitation, providing proprietary exosomes (Exomers and Plexaris) manufactured by Exopharm at clinical grade for the upcoming first-in-human clinical trials as part of the PLEXOVAL study.
1 Collins, A. Curr Pediatr Rep (2019). https://doi.org/10.1007/s40124-019-00198-1
2 Wiklander, O. P. B., et al. Sci. Transl. Med. 11, eaav8521 (2019)
3 Panagiotou, N., Wayne Davies, R., Selman, C. et al. Curr Pathobiol Rep (2016) 4: 181.
4 Yoshida et al., 2019, Cell Metabolism 30, 1–14 (2019)
5 Teo, K. et al. Cytotherapy 21, S52 (2019)
6 Batrakova EV, Kim MS. Wiley Interdiscip Rev Nanomed Nanobiotechnol. 8, 744-57 (2016)
7 Tian, Y., et al Biomaterials 35, 2383–2390 (2014).
8 Vituret, C., et al. Hum. Gene Ther. 27, 166–183 (2016).
9 Kalani, A. and Tyahi, N. Neural Regen Res. 10(10): 1565–1567. (2015)
10 Lee, S.-T., et al. J. Mov. Disord. 10, 45–52 (2017).
11 Cheng, M. Nature Communications 10, 959 (2019)
13 Woo, J., et al. Journal of Clinical Oncology 37, 18 (2019)
14 Lim, C. Z. J., et al. Nature Communications 10, 1144 (2019)