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

Exosome-laden Amniotic Fluid as Therapy

In the previous two posts, I covered aspects of a recently emailed ad from Apex Biologix I received in which they wanted everyone to know how safe and useful their Allogenic Birth Tissue amniotic fluid product is.

Relates Posts: Dissecting Ads for Regenerative Therapies: The Selling of Amniotic Fluid Products – Part One and Part Two

I took no issue with their obvious efforts to provide a safe product, but as I thought about their product, the gaps in our knowledge about amniotic fluid products became quite apparent. I also began to wrestle with the regulatory implications of exosome-laden amniotic fluid. Consequently, I will turn my focus away from specific products in this post and instead will consider the broader implications of using amniotic fluid therapy that doesn’t contain viable cells, but apparently is filled to the brim with exosomes.

Let’s start with a brief review of what exosomes are and what is known about the biomolecules they are known to contain. As indicated in Kalra, et al. (2016), exosomes are really small particles (30-150 nm) generated by most of the cells in our bodies. They contain various combinations of proteins, lipids, RNA and DNA as cargo. Exosomes have a bilayer plasma membrane, like most nucleated cells, but the composition of the bilayer differs from the parent cell from which the exosome is derived. Exosomes are found in a variety of biological fluids, including blood, milk, urine, saliva and amniotic fluid (Kalra, et al. 2016). It has been reported that more than 4,400 unique proteins have been identified in association with exosomes (Behara, et al. 2018).

Here’s a list of some of the types of biomolecules that can be found in exosomes and what they do (Iraci, et al., 2016):

mRNA: messenger RNA transfers genetic information to ribosomal RNAs during the generation of proteins, and have been shown to function in target cells

miRNA: microRNAs are able to silence genes in target cells

Lipids: a variety of lipids have been found in exosomes, which not only provide a stable exosomal plasma membrane, but some lipids interact with hydrophobic molecules to enhance their bioactivity and bioavailability

Proteins: several thousand unique proteins have been found in exosomes, including prion proteins (the kind associated with scrapie, which is similar to mad cow disease)

Viral particles: viral particles have been found associated with exosomes

From the list, it is possible to see a number of potentially positive benefits, like miRNAs silencing genes responsible for generating matrix metalloproteinases—the enzymes that degrade cartilage. Or exosomes could deliver mRNA from which proteins could be generated that might cause chondrocytes to proliferate. In fact, it would seem that anything is possible with exosomes, especially in the absence of hard data that might be applicable in the regenerative medical field.

From my reading, I believe there are a few important aspects of exosomes and the amniotic environment are worth considering:

  1. Exosomes are influenced by the environment in which the cells that release the exosomes reside. For example, if the cells are in a hypoxic environment, the exosomes might carry proteins or mRNA that reflect the stress the parent cells are experiencing.
  2. Virtually every cell in the body produces and responds to exosomes, and exosomes are a fundamental agent for inter-cellular communication.
  3. There are a variety of different types of cells found floating in amniotic fluid, including amniocytes, epithelioid and fibroblastic cells (Loukogeorgakis and De Coppi, 2016;).
  4. There are two types of stem cells identified in amniotic fluid: amniotic fluid stem cells and amniotic fluid mesenchymal stem cells (Loukogeorgakis and De Coppi, 2016).

Obviously, exosomes are found in amniotic fluid, but there are a lot of different types of cells that could be releasing exosomes, so the mere presence of exosomes shouldn’t be construed to mean that they all are therapeutically beneficial. During my review of recent exosomal literature, I still couldn’t find a single citation of a clinical study in humans demonstrating a therapeutic benefit from receiving donor-derived amniotic fluid exosomes.

The papers on exosomes I cited in this post point to the future value of exosomes in providing cell-free therapy to treat orthopedic pathologies. However, as best I can tell, none of the authors contemplate a massive program of treating patients with amniotic fluid. On the contrary, they are excited about the possibility of culturing cells—mostly MSCs at the moment—and recovering the exosomes released into the culture fluid. Clearly, the researchers and companies working on this type of therapeutic agent view exosomes as biologic drugs. Which leaves me scratching my head about the huge gap in knowledge between what the amniotic fluid hawkers know and what the rest of the therapeutic exosome world is working on.

The fact that no one knows what is contained in the exosomes found in amniotic fluid should be reason enough for exercising caution with these products. However, in the next post I will review potential issues associated with the donor-derived nature of amniotic fluid, which leads me to suspect not all is happiness and light with amniotic fluid products.

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