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

amniotic fluid therapeutic products

In the previous post, I raised the possibility that the FDA might view the presence of exosomes in amniotic fluid therapeutic products as causing the fluid to no longer be considered exempt from 21 CFR 1271, because the fluid with exosomes would no longer be considered as just a secretion. I had indicated that there were two questions that had a bearing on this issue. I will explore those questions in this post.

Do Exosomes Rely on Metabolic Activity of Living Cells for Their Primary Effect and Do They Act Locally?

The FDA considers an HCT/P to be governed by 21 CFR 1271, if it is donor-derived, but doesn’t have a systemic effect or depends on the metabolism of living cells. On the other hand, if it is donor-derived and either has a systemic effect or relies for its primary function on the metabolism of viable cells, the product no longer qualifies as a 1271-regulated HCT/P, but rather it becomes a drug or biological drug.

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

Let’s start with the mechanism of the hypothetical therapeutic benefit of exosomes found in amniotic fluid. Of course, no one knows exactly what therapeutic benefit, if any, might be associated with exosomes found in amniotic fluid, but there are a couple of possible therapeutic strategies laid out in the literature based on research with other sources of exosomes.

I have cited literature that established that exosomes frequently carry genetic material, including mRNA and miRNA. These nucleic acid sequence-containing components are inserted into the cargo hold of exosomes during the maturation process involved in forming and releasing the exosomes. mRNA is messenger RNA that encodes for the generation of proteins in a process known as translation. The generation of proteins based on the mRNA in exosomes has been shown to occur in target/recipient cells to which the exosomes bind. miRNA refers to short genetic segments that are able to silence the expression of genes, which also has been shown to occur in target/recipient cells.

I would contend that the presence of genetic bits and pieces derived from a parent cell enclosed in exosomes released by that cell constitute “metabolic activity of living cells”, since the genetic bits have been shown to alter the behavior of target/recipient cells. Modifying the behavior of other cells would seem to me to constitute a primary function, which is derived from donor cells even though those cells may no longer be present in the amniotic fluid.

Let’s consider the other potential issue that might trigger cell-free amniotic fluid products to be elevated to a biological drug status—systemic action. Proteins clearly are found in amniotic fluid therapeutic products, and when that fluid is injected into a site of pathology, they will be active for a few minutes to a few hours, since proteins are fairly easily removed by normal degradative pathways the body relies on to maintain homeostasis. In contrast, the cargos of exosomes are very well protected from degradation, and so they could persist for much longer. Longer persistence means that the exosomes could migrate away from the site of injection, and given how tiny they are, exosomes might end up in biological compartments quite distant to the treatment site. For example, exosomes are known to cross the blood-brain barrier (Kalra, 2016).

Thus, exosomes are a product of the metabolism of living cells, can act at a distance, and can influence target cells that will have no relationship to the cells that produced the exosomes in utero, since most recipients of amniotic fluid products containing exosomes will be treated for orthopedic pathologies. Inherently, the target cells are unrelated from the amniotic tissue cells that produced the exosomes. So, it isn’t obvious that the exosomes can perform the same basic function in the recipient as they played in the donor’s fetal/maternal tissue.

On the other hand, the FDA could examine the behavior of exosomes in light of the fact that that metabolic activity of living cells present in an HCT/P limits using those cells to treat the donor, or the close relatives of the donor. In this case, there are several elements of exosomes to keep in mind:

  • Exosomes result from the metabolism of living cells
  • Exosomes have a primary effect based on the contents of the exosomes established at the time of their dispersal from the parent cells—reflecting the metabolism of those cells
  • Exosomes don’t necessary remain local, since they are extremely small and protected from the normal degradative pathways the body has for maintaining homeostasis
  • Exosomes can act via genetic mechanisms (e.g., mRNA, miRNA), which are based on the binding of the exosomes to target cells, providing for a far-reaching influence over the target cell’s metabolism
  • Exosomal binding to target cells in orthopedic pathologies isn’t defined or known

Thus, exosomes are imprinted with all of the machinery found in their parent cells, so that they could be considered as functionally equivalent to living cells.

Will the FDA Define a New Regulatory Paradigm for Amniotic Fluid Therapeutic Products?

It could be that the FDA decides to fall back on its statement in the MM/HU Guidance that while the secretions of amniotic fluid are considered to be exempt from 21 CFR 1271 regulation, the cellular parts are considered to be HCT/Ps. In this case, since the exosomes are completely dependent on the metabolism of those (and other) cells, the FDA might consider them in essence to be cellular HCT/Ps.

Now that there are amniotic fluid product manufacturers announcing to the world that their amniotic fluid has exosomes in it, the very existence of exosomes in amniotic fluid might be the trigger that results in a determination that amniotic fluid therapeutic products that are full of exosomes should be considered to be biological drugs. Should the FDA get to this point, the regenerative medical community would see amniotic fluid products quickly disappear from the market place, since as a biological drug, these products would need to follow an IND pathway for Premarket Approval established by the FDA for drugs. The exosome is in your court, FDA.

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