Regenexx Blog
By Chris Centeno, MD / August 21, 2019

Click for video:
https://regenexx.com/blog/what-is-exosome-therapy/

You’ve probably seen that one of the hottest areas of regenerative medicine treatment right now is exosome therapy. So what is exosome therapy? What are exosomes exactly? Do exosomes have something to do with stem cells? How are exosomes made? Let’s dive in.

What are Exosomes Exactly?
what is exosome therapyExosomes are how cells talk to each other (1). They are also called extracellular vesicles. In the image shown here, note that Cell A has a bunch of these vesicles (small circles) that eventually leave that cell and travel to cell B. These exosomes have information in the form of chemicals (cytokines) to snippets of messenger RNA (m-RNA).

Put more simply, exosomes are how cells communicate. For example, we can communicate by writing small notes to each other electronically, otherwise known as email. Exosomes are a way for one cell to email another. The message may be how to behave or what’s happening in the local area or it can even be something like a computer virus that hijacks the other cell (mRNA).

Do Exosomes Have Something to Do with Stem Cells?
All of the cells in your body can email each other through exosomes and this includes stem cells. The excitement behind exosomes and stem cells comes from early research showing that the positive effects of stem cells on tissue repair could also be sometimes replicated if you just used the media in which the cells were growing and got rid of the cells (2). It was believed that this happened through the cytokines (chemical messenger molecules) in the media as well as exosomes. Hence, the idea began that it may be possible to help patients heal without stem cells, but by using only the exosomes that the stem cells produce.

How are Exosomes Made?
Exosomes are commonly made by growing stem cells in culture and then taking the media (liquid) in which they grow and then getting rid of the stem cells. The media is then ultra-centrifuged since the exosomes are small. This can concentrate the exosomes.

What is Exosome Therapy?
In the last few years, we have begun seeing companies producing exosome products for doctors to use on patients. While there is still regulatory uncertainty as to whether this is legal (more below), some doctors have begun using these products on patients. The most common uses of exosomes currently are to treat orthopedic injuries and for anti-aging. The exosomes are usually injected into the area in need of treatment, like the knee, or given intravenously for anti-aging. The idea is that they will promote tissue repair.

Does Exosome Therapy Work?
While exosome therapy is becoming more common, are there any clinical trials that show that exosomes can help patients? Let’s start with knee osteoarthritis. While I found an animal study that looked promising (4), there is no clinical research on the use of exosomes to treat knee arthritis in real patients. As you may know, the percentage of drugs that work in animals and then are later shown to be effective in humans is small.

The research on the use of exosomes for anti-aging is even less developed, with a single mouse study showing that this could work (5). Note that this type of exosome therapy has nothing to do with the types of exosomes on the market today, as it was engineered to deliver a specific chemical (eNAMPT). Hence, we don’t have even a mouse study that shows that what you could be treated with today in a clinic would help reduce aging.

Mixed Messages?
A challenge in using exosomes clinically to help specific diseases is that the exosome messages that cells send to one another are context-specific. This means that if I’m growing stem cells in a lab, the cells are sending emails to each other that don’t really apply to how to fix a damaged knee. As an example, let’s say you hired a general contractor to redo your basement and he or she sends loads of emails to subcontractors on what to do, how, and when. You can’t send these same emails to your neighbor who wants a new kitchen so that he can skip hiring the general contractor. The subcontractors that your neighbor hires will have no idea of how the emails about your basement apply to your neighbor’s kitchen. To learn more about this, see my video below:

This is a big problem with commercially available exosome products today. They aren’t tuned to fix a knee or make you live longer, they’re just random messages from stem cells growing in culture. This is different than a stem cell who can act as a general contractor and detect what needs to be done and then send out exosome emails to the neighboring cells on how to repair the damage.

The FDA and Exosome Therapy
We have a couple of companies that have begun to market exosomes in a vial. These are either taken from amniotic fluid or from stem cells growing in culture. Both may have issues from a regulatory standpoint. Meaning both isolating exosomes and growing cells in culture to produce a product is considered more than minimal manipulation, which requires an FDA drug approval with clinical trials (6). This is directly from the FDA on this topic:

“Thank you for your follow-up inquiry regarding exosomes. Exosomes that are derived from amniotic fluid as you have described are human cells, tissues and cellular and tissue-based products (HCT/Ps) regulated as drugs and biological products under section 351 of the Public Health Service Act and the Federal Food Drug &Cosmetic Act (FD&C Act) in the Office of Tissues and Advanced Therapies (OTAT) in CBER and require premarket review and approval.”

In both cases stated above, the companies manufacturing these exosome products have decided to register them using the incorrect FDA pathway (donor tissue laws) (7). This means that there is no FDA prior approval for the product as is required, so existing exosome products are not “FDA Approved”. Hence, it’s buyer beware as far as what you’re getting.

Product Variability
Patients and doctors alike often place very different products into a single category. In this case, the idea of exosomes encompasses lots of different things. As you learned above, exosomes can come from sources like the amniotic fluid that surrounds a baby or even from stem cells growing in culture. For the later, just varying the culture conditions a little bit can result in completely different exosome messages (8,9). In fact, at this point, we’re not 100% certain what all of these exosomes do. Hence, one exosome product produced one way may be effective while another produced in a slightly different way may be ineffective. Hence, as a patient, I would need to see clinical trial results produced with the specific exosome product that was planned for my therapy.

The upshot? The concept behind exosomes shows much promise, but so far, we have no clinical data in humans that show that these products work. Frankly, there isn’t even animal data on the specific products being sold. Hence, right now, if you get treated with exosomes, you’re the experiment.

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References:

(1) H Rashed M, Bayraktar E, K Helal G, et al. Exosomes: From Garbage Bins to Promising Therapeutic Targets. Int J Mol Sci. 2017;18(3):538. Published 2017 Mar 2. doi:10.3390/ijms18030538

(2) Osugi M, Katagiri W, Yoshimi R, Inukai T, Hibi H, Ueda M. Conditioned media from mesenchymal stem cells enhanced bone regeneration in rat calvarial bone defects. Tissue Eng Part A. 2012;18(13-14):1479–1489. doi:10.1089/ten.TEA.2011.0325

(3) Gurunathan S, Kang MH, Jeyaraj M, Qasim M, Kim JH. Review of the Isolation, Characterization, Biological Function, and Multifarious Therapeutic Approaches of Exosomes. Cells. 2019;8(4):307. Published 2019 Apr 3. doi:10.3390/cells8040307

(4) Wang Y, Yu D, Liu Z, et al. Exosomes from embryonic mesenchymal stem cells alleviate osteoarthritis through balancing synthesis and degradation of cartilage extracellular matrix. Stem Cell Res Ther. 2017;8(1):189. Published 2017 Aug 14. doi:10.1186/s13287-017-0632-0

(5) Yoshida M, Satoh A, Lin JB, Mills KF, Sasaki Y, Rensing N, Wong M, Apte RS, Imai SI. Extracellular Vesicle-Contained eNAMPT Delays Aging and Extends Lifespan in Mice. Cell Metab. 2019 Aug 6;30(2):329-342.e5. doi: 10.1016/j.cmet.2019.05.015.

(6) HUMAN CELLS, TISSUES, AND CELLULAR AND TISSUE-BASED PRODUCTS 21 CFR § 1271.10

(7) US Food and Drug Administration. “Tissue Establishment Registration” 11 August 2019, https://www.fda.gov/vaccines-blood-b...t-registration.

(8) Showalter MR, Wancewicz B, et al. Primed mesenchymal stem cells package exosomes with metabolites associated with immunomodulation. Biochem Biophys Res Commun. 2019 May 14;512(4):729-735. doi: 10.1016/j.bbrc.2019.03.119.

(9) Willis GR, Kourembanas S, Mitsialis SA. Toward Exosome-Based Therapeutics: Isolation, Heterogeneity, and Fit-for-Purpose Potency. Front Cardiovasc Med. 2017 Oct 9;4:63. doi: 10.3389/fcvm.2017.00063.