Exosomes: The Rising Star

Until recently only a handful of researchers gave thought to these tiny bubbles released from cellular couriers that are packaged with molecular mail which race through the bloodstream. These exosomes shuttle proteins and genetic information between neighbouring and distant cells; now many scientists position to use them as a widespread tool for drug delivery.

Until recently only 508 papers referred to exosomes according to PubMed, now in site searches bring over 8,000 hits which includes several high profile publications. Exosomes were viewed as tiny trash sacs tossed from cells until Jan Lotvall showed that some cells used exosomes to transfer genetic materials in 2007; a discovery which has scientists now searching for ways exosomes may be involved in health, disease, and used as treatments.

Exosomes are implicated to be involved in spreading diseases such as cancer and metabolic conditions, a recent study points to the vesicles as a culprit for disrupting amyloid-B proteins that accumulate in the brains of those with Alzheimer’s disease. Exosomes can so easily carry molecules that spread disease, science is working on developing ways to hijack this ancient messenger system to carry molecules to stop disease.

Manipulating exosomes may solve drug delivery problems for a wide array of therapies including small molecules, RNA therapies, proteins, viral gene therapy, and CRISPR gene editing tools. Other research is capitalizing on the exosomes themselves when derived from stem cells they could become a branch of regenerative medicine technology.

Big pharma has even started to use this technology, while some say we are close to understanding the biology but are far off from therapeutics and diagnostics; exosome based cancer diagnostics are already available and multiple exosome therapies may begin clinical trial testing in the near future.

Cancer biologists at the University of Texas are using exosomes to successfully deliver an siRNA therapy to cancer cells in mice; such work has potential to overcome the ongoing problem of getting siRNA into the right cells that has long vexed scientists. Synthetic lipid nanoparticles are used as delivery device but they can cause toxic immune responses, although their design has improved they remain notorious for congregating in the liver limiting the kinds of disease they can effectively target.

Many exosomes may also gather in the liver, but significant numbers do manage to travel to other organs, including the pancreas, and have been used to block production of mutant KRas proteins in one of the most undruggable cancer targets according to Raghu Kalluri, in which intravenous injections of siRNA loaded exosomes suppressed pancreatic cancer in mice more effectively without any obvious immune reactions than similar injections using nanoparticles.

The field of exosomes is expanding rapidly with more and more companies sprouting up such as Evox Therapeutics which is developing exosome based treatments for rare diseases, particularly those that require delivery to the brain; and Anjarium Biosciences developing hybridosomes which are a mix of synthetic lipid nanoparticles and natural exosomes. Massachusetts General Hospital has packaged vexosome adeno associated virus gene therapy inside exosomes to use for transport to cells that have proven hard to reach such as sensory cells in the inner ear. Another team uses a larger cousin of exosomes called microvesicles to deliver proteins, mRNA, and CRISPR/Cas9 gene editing into cells.

Should exosomes prove to be efficacious drug delivery vehicles their success will likely stem from their compatibility with the human body, which is why many are also looking for alternative sources of natural exosomes.

Boston Children’s Hospital scientists have been trying to tap stem cell potential to create regenerative therapies for newborns with damaged lungs, demonstrating MSCs can treat animal models of lung disease via reducing inflammation and repairing lung tissue. First guesses suggested MSCs worked by melding with damaged tissue and becoming lung cells, further investigation revealed donor stem cells don’t stick around causing a paradox;  until 2012 when their research finally showed extracellular vesicles released from NSCs were preventing lung damage in mice. The team continued investigations learning how to isolate and purify exosomes from stem cells to show in 2018 that MSC derived exosomes are responsible for healing effects in mice with serious lung disease. Talks are underway with the US FDA to use exosomes to treat bronchopulmonary dysplasia in newborns.

It is not clear what molecules inside exosomes have therapeutic properties in many cases, but that has not stopped companies from turning to exosomes such as Capricor Therapeutics founded to develop stem cell therapies derived from heart tissue to treat cardiac and inflammatory conditions. AruanA Biomedical has tested exosomes derived from human MSCs and neural stem cells in animal studies reporting improved preservation of brain cells and motor movement; clinical trials in humans could begin in 2020.

Rogue stem cell clinics are taking less cautious approaches and are forgoing traditional clinical trials and FDA approval taking their treatments straight to consumer demand with unproven claims of aiding in aesthetics, immunotherapy, erectile dysfunction and much more. Exosomes and stem cells show great promise and have worked in animal studies, however success in humans has been harder to find, and what make them therapeutic still remains unclear. Many experts suggest we should try to understand the mechanism more before rushing therapies as to not setback the field.

As biotech firms and academic labs push forward with exosomes to deliver therapeutics or as therapeutics they are being presented with waves of technical issues such as making enough of the vesicles themselves. Extracellular vesicle diversity is another issue, once there were only two major classes but now it has been realized there are many and we don’t yet know how to separate them, complicating experiments, explains Xandra O. Breakefield.

Some startups are starting to look for new kinds of exosomes from plants, fungi, bacteria, and animals, with some trying to develop fruit derived exosome therapies to deliver cancer drugs. Pharma is paying attention too with Roche paying $36 million for access to PureTech Health for access to its exosomes extracted from dairy cow milk. Roche plans to package exosome antisense oligonucleotide therapies for oral delivery believing it to have widespread application.

Exosome therapies are being developed to tackle different diseases using different exosomes, and they are doing it quickly, which could either catapult the field forward or possibly make it difficult to troubleshoot as problems arise, as was the early days of gene therapy.

This is both an exciting time and a dangerous time, as if there is a product released with confidence of it working, if things go wrong it will set the entire field back. Most scientists have migrated towards exosomes as result of chasing down the basic biology of disease, developing diagnostics, or trying to find a better drug delivery method; which speaks to the fact that exosomes are important to almost every aspect of biology and medicine, and of exosomes carrying huge potential.