Today, exosomes are increasingly being investigated as a novel class of therapeutics that could explain the functions of many types of traditional cell therapies. To explain this trend, we contacted an esteemed exosome researcher, Dr. Ramon Coronado Schmilinski. Dr. Coronado Schmilinski was the previous Executive Director at Lester Smith Medical Research Institute and is the current VP Regulatory Affairs and Technology Transfer at Signature Biologics.
In this interview, we discuss how he started working with exosomes while looking for mechanisms used by MSCs to exert their therapeutic effects. We discuss the scientific importance of exosomes, their therapeutic and diagnostic applications, and how exosomes are being used within encapsulation and delivery systems.
Read on to learn how these extracellular vesicles could transform the future of modern medicine as we know it.
Interview with Dr. Ramon Coronado Schmilinski
Cade Hildreth: What is your background and how did you become involved with exosomes from perinatal tissues?
Dr. Ramon Coronado: I completed my B.S. in Biomaterials /Polymer Engineering in my native country of Venezuela. Later, after which I came to the U.S. to complete my Masters and Ph.D. degrees in Biomedical Engineering. While working on my Ph.D., in a collaborative effort between the U.S. Army Institute of Surgical Research, the University of Texas at San Antonio and the UT Health San Antonio transplant center, I completed a Graduate Certificate in Technology Entrepreneurship and Management that taught me about the industry side of biologics as well.
I believe that mentioning where I was trained is important, because this conglomerate of institutions gave me the tools to start my first business, Mobile Stem Care, which isolated stromal vascular fraction cells from a pet’s adipose tissue, delivering those cells via infusion to treat a myriad of conditions.
I have seen first-hand how powerful this type of cell therapy can be and I have also seen circumstances in which the outcome was negligible, and that brought a certain degree of frustration. In trying to find resolution to that frustration, I have been pursuing understanding of mesenchymal stromal cells’ (MSC) mechanisms and how these cells work.
Later, as the Director of the Lester Smith Medical Research Institute over 5 years I pursued a commitment to answering the questions:
- How mesenchymal stromal cells work?
- Which cells are responsible of that therapeutic effect?
The reason why I care is simple, and it is something with which the pharmaceutical industry is familiar: identifying the mechanism(s) of action at work. For example, during early stages of pharmaceutical development, herbal medicine was used in a raw form until we understood how it worked and which molecule was responsible of acting as a drug. Then, the active molecule was isolated, purified and concentrated, giving us a more reliable, safe and dependable drug.
Like the early phases of the pharmaceutical industry, I believe we are in a similar stage when we talk about mesenchymal stromal cell therapies. Once we understand how it works in a “raw” form and what is the active ingredient, we will then be able to have a more dependable and safe treatment.
The line of research, I am continuing to lead the way to investigate now with the enhancement and support in joining Neil Riordan, PhD. and Jonathan Hernandez, PhD. at Signature Biologics in Dallas, TX. Here we are investigating mechanisms of action around regulation of immune response, inflammation, and autoimmune disease. An important part of our work is dedicated to understanding how MSCs can be used to promote immune tolerance while diminishing the use of immunosuppressants. Hence, we have focused to use the sources of MSCs that are naturally involved in these processes, which is the perinatal tissue (around the fetus).
The mother tolerates the fetus, even if it is a “foreign” entity, there is an innate capability of the fetus to signal the mother’s immune system to avoid being attacked. We are now trying to understand how that is possible and if we can emulate that behavior in a different adult setting. That is how I started studying perinatal cells.
Over time it has become evident that perinatal cells are easier to obtain in high numbers than many other MSCs sources. You can find more in the Perinatal Stem Cell Book (https://www.elsevier.com/books/perinatal-stem-cells/atala/978-0-12-812015-6)
Cade Hildreth: When did you start working with exosomes and why?
Dr. Ramon Coronado: I started working with exosomes while looking for mechanisms used by MSCs to exert their therapeutic effect at Lester Smith Medical Research and have expanded my work now at Signature Biologics.
There are few key components, or clues, that led me to be immensely interested in exosomes, which include:
- Some researchers have been able to obtain similar therapeutic outcomes by only using the condition media compared to using cells.
- It is evident that some of the MSCs effects can be observed by using co-cultures in which cell to cell contact is not permitted.
- The effect of MSCs can be observed without having any cell grafting and/or differentiation.
- A certain degree of gene therapy has been observed, where exosomes can modify the genetic make-up of the exposed cell, similar to gene transfection.
Cade Hildreth: With what types of perinatal tissues do you work?
Dr. Ramon Coronado: We work with traditional MSCs from virtually all tissues of the placenta, MSCs from chorion, cord, amnion, villi, etc. We also have great interest in other perinatal stem cells that are not classified as traditional MSCs, however those have posed some challenges to culture in vitro.
Finally, we have created few cell lines and isolated subpopulations of the above-mentioned cell groups.
Cade Hildreth: What methods do you use for isolation of exosomes from these materials?
Dr. Ramon Coronado: We are currently using centrifugation methods, filtration, and chemical precipitation. We are working on technologies that would allow us process high volumes at the time.
Cade Hildreth: What are therapeutics applications of these exosomes?
Dr. Ramon Coronado: To be clear, all these technologies are clearly in the research stage only and it is early to be certain about all possible applications, but without a doubt this is a disruptive field. At Signature Biologics, we are pursuing avenues with respective Regulatory Authorities in key markets where we will, in partnership with those authorities, seek regulatory approvals for areas of study as required.
There are two major families of technological applications where I can see exosomes being used:
- Diagnostic agents
- Therapeutic agents
The use of exosomes for diagnosis has been without a doubt its most investigated application, specifically their potential as biomarkers. Remember that exosomes are seen as the “mail” used by cells to communicate throughout the body, hence, intercepting and “reading” these letters is known to provide a great deal of information. However, there are still plenty of studies needed to completely understand the meaning of those letters.
Regarding the therapeutic world, I believe the exosome field is about to truly explode. The opportunities are many. For instance, using the previous example, you can now “write” and deliver selected “letters” with the pertinent information to modify a biological pathway. Take for example immunology. You could now “communicate” to immune cells to behave in a tolerance state and perhaps diminish autoimmunity.
In addition, exosomes can be engineered to target specific organs/tissues/cells, since they can be designed to be enriched with transmembrane proteins/ligands/homing peptides on their surface. The challenge remains though to know what is in those “letters” which also effectively means one needs to understand the mechanism of action at work.
Mesenchymal stem cell exosomes are also very attractive for drug encapsulation and delivery, since their encapsulation and delivery efficiency are much better than any other artificial drug delivery system. If used as gene therapy encapsulation/delivery system, exosomes have low toxicity, low immunogenicity, great stability inside the body and are permeable to many biological barriers.
Exosomes have the capability to turn biological processes “on” and “off” using miRNA and other peptides. I believe there will be a plethora of applications that take advantage of exosome properties, from regenerative applications to vaccines, cancer, aging, diagnosis, inflammation, autoimmune, etc. For example, there are already companies that are heavily funded, using exosome strategies to prevent cancer metastasis.
Cade Hildreth: What are advantages associated with using perinatal exosomes over perinatal cells?
Dr. Ramon Coronado: The main advantage of exosomes over cells is that they are not alive. For translational science, this component is of great importance. For example, if you are working with manufacturing and delivering exosomes you don’t have to worry about viability. Simplifying the lab-to-patient supply chain with technologies including exosomes can be a great advantage to the proliferation of these therapies when they are approved in their respective markets.
From the business point of view this can be a tremendous advantage, since exosomes can just be frozen without having to use cryo-preservatives that sometimes can bring translational hurdles. On the other hand, cells could be a superior therapy, since they can adapt and respond to challenges found within the body, prompting a stimulation required to provide a robust therapeutic effect. It has not been fully elucidated how cells exert their therapeutic effect, spurring on our quest for knowledge in this field, with the intention to move from cells to exosomes.
Another advantage of exosomes over cells is that they have a “fixed” molecular profile once released from cells, which allow us to better study them. Even though they have a myriad of molecules, they are still less complex compared to cells with their dynamic molecular profiles.
In addition, exosomes are more flexible with regard to routes of administration. The field is still evaluating efficiency while comparing routes of administration, but it seems that exosomes can be delivered orally, intra-muscularly, IV, and subcutaneously, as compared to the limited routes of administration available for cells.
When dosing, due to the nature of the product (non-living, flexible route of administration, low immunogenicity, biocompatible, etc.) exosomes could be dosed more repeatedly, consistently, and possibly without medical expertise in some cases, in comparison compared to cell infusions for example.
Last, another benefit is that if we can understand which molecule or exosome profile is needed for a therapy, we could then produce them more consistently by designing a cell line that can “manufacture” exosomes according to the therapeutic needs. This means more predictable and standardized elements that could help in fulfilling regulatory requirements for clinical manufacturing. Both cellular and acellular therapies face the same challenge: documenting the active mechanisms of action at work, but acellular therapies may have a logistical advantage as outlined here.
Cade Hildreth: Are there any disadvantages associated with the use of exosomes?
Dr. Ramon Coronado: For therapeutic purposes, yes. First, isolation and manufacturing are far from practical; although it is better than cell manufacturing, in my opinion. There have been a lot of advances in this area and we’re excited to see how final products, CMC, and processing procedures will contribute to the therapies to solve this prior gap.
Second, it is possible that the dose needed for therapeutic benefits is unattainably high using current technology. In addition, it is possible that exosomes alone (compared to condition media for example) are not sufficient to exert complete therapeutic effect. The areas of exosome use, and clinical efficacy require much more study and sponsorship to tackle the big questions.
For diagnosis purposes, I cannot see many disadvantages. However, I am not strongly involved in that field. Samples can be obtained from any fluid (urine, saliva, blood, tears etc.) and the required volumes are small. It does not get much better than that.
Cade Hildreth: How do you think the FDA will treat regulation of therapeutic exosomes?
Dr. Ramon Coronado: First, there are currently no FDA-approved exosome products. FDA has been a very reliable partner in communicating the regulatory framework for exosomes. They provided clear examples for industry in the November 2017 Guidance to Industry on HCT/Ps which they have improved upon in December of 2017, and summer of 2020.
Further, FDA has proactively communicated with industry and patients in December of 2019 onwards with Public Safety Notices and clearly identifying that exosomes used to treat diseases or conditions in humans are regulated as drugs and Biologics under the Public Health Service Act and the Federal Food Drug and Cosmetic Act which makes them subject to premarket review and approval requirements.
With my new capacity at Signature Biologics, regulatory adherence and the technology transfer are chief priorities for me and the organization. We are excited to follow guidance from FDA and partner with them through the premarket approval pathways to ensure safe and efficacious therapies are available in the United States.