Extracellular vesicles in drug delivery – Understanding their potential and challenges

Jörg Schneider | Associate Principal Consultant, Biopharma Excellence

The field of extracellular vesicles (EVs) – is a nascent and rapidly evolving one, often posing more questions than answers when it comes to determining their therapeutic potential.
“The term extracellular vesicles is really an acknowledgment that we’re just working with a heterogeneous population of vesicles produced by all manner of possible mechanisms,” said Dr. Steven Jay, associate professor of bioengineering at the University of Maryland in an FDA webinar published in 2020.

What are EVs?

EVs are nanoscale, membrane-bilayered, delimited particles. They are ubiquitous, appearing in almost all cells and tissues, including milk, urine, blood, the reproductive tract and many other bodily fluids.

EVs were initially thought to function mostly as a waste disposal mechanism for cells until further research discovered their more significant role in intercellular communication. That discovery led to interest in their potential as therapeutics, which inevitably led to widespread interest in the field.

Scientific rigor

Amid concerns that claims in some articles on the subject lacked sufficient rigor, the International Society for Extracellular Vesicles (ISEV) published a position paper in 2014 with recommendations on “minimal experimental requirements for definition of extracellular vesicles and their functions.” The list covered EV separation and isolation, characterization and functional studies.

In 2018, the ISEV board revised the recommendations, with clearer explanations of the need for each recommendation as well as greater detail. For example, in 2014 ISEV provided no recommendation on quantification as a step for characterization, whereas the 2018 update states that both the source (for example the number of cultured cells) of EVs and the EV preparation must be described quantitatively.

What is striking about the updated recommendations is just how rapidly the field has developed and the exponential growth in the number of applications for EVs.

Most recently, more concrete considerations for the development of EVs as investigational medicinal products for early clinical trials were published in a position paper to support transition from research to clinical development.

The therapeutic potential for EVs

There are two main branches of EV application: The first is for immune modulation, with applications as diverse as vascular repair, osteoarthritis skeletal muscle myogenesis, hair growth, spinal cord injury and wound healing.

The second is as a delivery vehicle, an area that has attracted growing interest, but with it many more questions. First, researchers must grapple with how best to load EVs in the delivery vehicle – a challenge, given there is, as yet, no standard reporting framework concerning their loading for drug delivery. One way is to make the source cell recombinant in such a manner that, for example, an RNA ends up in the vesicle. However, that poses a further question, which is how do you control quantity? Another way would be to isolate the vesicles before loading them. Again, this poses questions: Did the loading modify features of the end product or the loaded vesicles? And how would you characterize this modification? How do you know the product is in there? Does it have an impact on characterization markers?

In his talk, Dr. Jay highlighted the growing interest in EVs as an alternative to cell therapy. “Given the role of EVs in intercellular communication, it’s now been recognized that, in certain cases, EVs are playing the most significant role in mediating any paracrine effects from transplanted cells,” he said.

Several companies have begun clinical trials into EV therapeutics, including Codiak Biosciences, Capricor Therapeutics and Aegle Therapeutics. For example, Codiak has built a proprietary platform for engineering exosome therapeutics.

Currently, no products involving EVs have been approved by regulatory authorities. Nevertheless, excitement over the potential of EVs remains, and there are currently around 60 interventional trials recorded on ClinicalTrials.gov with exosomes and EVs.

Support for EV innovation

As the opportunities for EV application grow, so too do the supporting industries and initiatives such as the ISEV Task Force on Regulatory Affairs and Clinical Use of EV-based Therapeutics and the Exosomes Committee from the International Society for Cell & Gene Therapy. A growing number of service providers are offering their expertise in this field, including CROs with specific and dedicated offerings, particularly in the highly complex CMC area. Equally, there is a need to understand and support the highly complex and rapidly evolving regulatory challenges. That is because the range of potential uses of EVs means the regulatory classification in different jurisdictions will depend on what they are being used to deliver, and that in turn impacts regulatory and development plans.

Innovators and service providers – CROs, compliance experts, and so on – eagerly await specific regulatory guidelines for exosome therapies. In the meantime, the best alternative is to leverage safety standards for cell and tissue-based products as roadmaps for EV-based therapeutics.

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