Implications of Using Donor-derived Exosome-laden Amniotic Fluid As a Therapy: Practical Concerns and Potential Regulatory Issues – Part Two

Exosome-laden Donor-derived Amniotic Fluid

In the previous post, I reviewed some aspects of exosomes: what they are, where they come from and the lack of human clinical studies showing efficacy in treating orthopedic pathologies. The papers on exosomes I reviewed pointed to a bright future for using exosomes as therapeutic agents, but the approach they were advancing is to produce exosomes under controlled culturing conditions, purify them, characterize them and do the clinical studies needed to show their value, as required for therapeutic agents considered to be drugs. The presence of exosomes in donor-derived amniotic fluid is gaining attention in the commercial world, which is quite different from creating drugs composed of exosomes, which will take years to come to market.

But if you are eager to get your hands on exosomes right now, your only option is to contact a hawker of amniotic fluid. The company whose ad I reviewed previously (Dissecting Ads for Regenerative Therapies: The Selling of Amniotic Fluid Products – Part One and Part Two) will sell you donor-derived amniotic fluid without viable cells and no micronized tissue, proclaiming that it is okay to use for homologous purposes. Unless you limit your practice to really pregnant women, I am not sure what a homologous use for amniotic fluid would be. The fact that some amniotic fluid products lack both viable cells and micronized tissue might make you feel better, since amniotic fluid by itself isn’t governed by 21 CFR 1271—the rule controlling such popular therapeutic agents like adipose tissue. On the other hand, at the risk of raining on the exosomal parade, I would like to point out a couple of scenarios that have the potential to be problematic with donor-derived amniotic fluid products.

In the list I shared in the previous post, you will notice I mentioned a specific type of protein, identified as prions, which have been found in association with exosomes (Iraci, et al., 2016 ). Prions are responsible for very nasty neurodegenerative diseases like scrapie in sheep or Creutzfeldt-Jakob disease in humans. And to quote Iraci, et al. (2016): “…exosomes have recently been proposed as the Trojan horses of neurodegeneration…”, meaning that sometimes exosomes carry potentially dangerous cargo. While the presence of individuals infected with prion-associated diseases is very low, the fact is exosomes are capable of spreading prion disease within individuals, so why couldn’t exosomes in amniotic fluid spread prion disease to recipients? As best I can tell, testing of donor-derived amniotic fluid required by the FDA doesn’t include checking on the presence of prions. While I agree there may be a very small chance that exosomes in amniotic fluid might give you a neurodegenerative disease, the lack of testing for this type of infectious agent is disconcerting.

If you consider my concern for exosome-linked transmission of prion-based diseases to be an overreaction, I offer up the situation with Zika virus. Women who are exposed to the Zika virus and become pregnant run a risk of passing the infection on to the fetus, which can result in substantial birth defects, including microcephaly. It seems to me if the fetus can become infected, it is quite possible that cells in the placental tissues associated with the fetus also could become infected. So, let’s say that amniotic fluid is collected from a woman unknowingly infected by Zika virus. Could the exosomes present in the amniotic fluid carry the Zika virus? As pointed out in Iraci, et al. (2016), exosomes have been shown to contain viral particles as cargo.

Let’s say that exosomes found in amniotic fluid could carry Zika viral particles. You get an injection of the infected exosomes found in a particular lot of amniotic fluid, thereby exposing yourself to the Zika virus. In most folks this is a mild, though somewhat discomforting, infection that will last for a few days. If you engage in sexual relations while unknowingly infected, the CDC has indicated you could pass the infection on to your partner. Let’s say you and your partner are trying to have a baby and while you are infected with the Zika virus, she gets pregnant.

This scenario might seem far-fetched, but Zika viral contamination is taken very seriously at the FDA. For example, although detectable cases of Zika virus in the USA have dropped considerably over the past couple of years, the FDA requires that donated whole blood be tested for the presence of Zika virus. Furthermore, CBER has indicated they will publish a draft guidance on testing HCT/Ps for Zika virus by the end of the year.  So, you might say, nothing to worry about. However, amniotic fluid without viable cells isn’t considered by the FDA to be an HCT/P. Although, the FDA might consider the “original HCT/P” to be cell-filled amniotic fluid in utero, which means that all donor-derived amniotic fluid products would require testing. Apex Biologix, in their ad, indicated that every lot of amniotic fluid was tested for various contaminants, including HIV, and Hepatitis B and C, among other infectious agents, so it very well could be that Zika virus will be added to the list.

The message I hope to convey is one of concern over the enthusiastic embrace of amniotic fluid products full of exosomes. Nothing much, if anything, is known about the genetic components contained in amniotic fluid-derived exosomes, and certainly there is no clinical evidence that exosomes present in donor-derived amniotic fluid have any beneficial properties for treating orthopedic pathologies. Importantly, exosomes have been shown to participate in the spread of neurodegenerative diseases (via prions) and can carry viral particles.

Some of you might argue that there always are inherent risks when using any donor-derived biological tissue, which is precisely my point. But in the rush to celebrate this shiny, new therapy, I believe there is significant uncertainty as to the risks associated with the very thing that the hawkers of amniotic fluid now are promoting: exosomes.

The cell-free, donor derived-amniotic products I have been discussing over the past few posts are considered to be `361 category products, meaning that the products don’t need to undergo a pre-market approval process prior to marketing and sales. However, I will explore in the next couple of posts the possibility that exosome-laden amniotic fluid might be a `351 category product, meaning that these products would be considered a biological drug by the FDA, requiring a full series of clinical studies prior to marketing.

Leave a Reply