Peek behind the paper: Mesenchymal stem cell use in acute respiratory distress syndrome: a potential therapeutic application
In this peek behind the paper, Julien Freitag discusses his recent article “Acute respiratory distress syndrome and the potential therapeutic application of mesenchymal stem cells”, published in Future Science OA.
Can you introduce yourself and tell us a little about your role?
I am a musculoskeletal physician and hold an adjunct Associate Professor position at Charles Sturt University (Melbourne, Australia) in the area of Biomedical Sciences. I am the Head of Clinical Research at Melbourne Stem Cell Centre (Australia) and Head of the Clinical and Scientific Advisory Board of Magellan Stem Cells (Melbourne, Australia).
I am also the principal investigator in a number of translational research projects assessing the clinical application of mesenchymal stem cell therapy. I have recently published the first randomized-controlled trial on the use of adipose-derived mesenchymal stem cells (MSCs) in the treatment of knee osteoarthritis.
How does acute respiratory distress syndrome (ARDS) affect a patient’s lungs?
ARDS is a condition whereby an uncontrolled inflammatory cascade causes progressive lung tissue injury leading to increased cell lining permeability, alveolar fluid collection and resultant pulmonary edema (fluid in the lungs). ARDS may occur as a result of lung infection (as seen in COVID-19), sepsis, trauma, aspiration or drug reaction.
The increased fluid within air spaces seen in pulmonary edema leads to impaired gas exchange and may lead to respiratory failure. Left untreated, pulmonary edema can result in fatal respiratory distress or cardiac arrest as a result of hypoxia.
What current treatment is available for ARDS?
Current treatment primarily involves treating the underlying cause (i.e., treatment of lung infection) and supportive care. In the early stages of ARDS, supportive care may involve non-invasive ventilation, though progressive ARDS will require assisted mechanical ventilation via intubation. Additional supportive care measures include a conservative fluid-management protocol and placing the patient in a prone position. Extracorporeal membrane oxygenation is a technique that may be utilized – where available – if inadequate oxygenation is achieved with mechanical ventilation. In effect, these supportive measures are continued until the patient recovers from the underlying cause and the lung tissue heals with resultant improvement in lung function. Unfortunately, despite our increasing understanding of the cause of ARDS, the success of supportive measures is limited and ARDS has a reported mortality rate of up to 40%.
Why are MSCs considered a possible treatment?
ARDS is characterized by an unregulated inflammatory cascade resulting in lung tissue injury, pulmonary edema and impairment of gas exchange leading to respiratory failure. Whilst interest in MSCs was initially due to their ability to differentiate along a mesodermal lineage, it is now accepted that their primary mechanism of action is via both paracrine mechanisms and cell-to-cell interaction. MSCs are observed to have an effective immunomodulatory role with inhibition of monocytes and suppression of inflammatory T-cell proliferation. In addition to this they express an array of anti-inflammatory cytokines and additional bioactive molecules that may stimulate local tissue repair. In effect, MSCs, through direct interaction with the local environment, may be able to ameliorate the uncontrolled inflammatory cascade seen in ARDS and additionally assist in repair of lung tissue.
What are the challenges in developing an MSC treatment for ARDS?
The development of an MSC therapy for ARDS poses a number of challenges including overcoming widespread misunderstanding of cellular therapies in both the clinical and general population.
ARDS is a life-threatening condition with poor prognosis and currently strong efforts are being made globally to look at ways to salvage patients particularly affected by COVID-19-related ARDS. Whilst the evidence and safety data points to MSC therapy as a promising modality, proposed trials are at risk of being overshadowed by conventional repurposed therapies, which in some cases may be less promising but accepted as priority due to their familiarity.
In broad terms development of an MSC therapy poses additional challenges with regards to consideration of variables including cell source, cell potency and dosing, and mode of delivery. Additionally, despite systematic review of clinical trials involving MSC therapy indicating safety with no observed serious adverse events, there remains concern regarding MSC ability to migrate to a site of cancer and promote cancer growth. Surprisingly, MSCs have been shown in some cases to inhibit rather than encourage cancer growth. These areas highlight the importance of structured trials with use of methodology consistent with MSC’s mechanism of action to ensure both effective and safe development.
In addition to challenges in trial design there are obvious economic and regulatory hurdles in the development and implementation of MSC therapy. Whilst some cell technologies may be overlooked by industry due to cost of development, it is pleasing to see that despite this economic hurdle the apparent medical necessity and potential impact on patient outcome has seen significant advances being made in MSC therapy development for ARDS during the current COVID-19 pandemic. Complementing this, government regulatory bodies have more recently recognized the importance of development in areas such as ARDS where current treatments are limited and patients are otherwise at high risk. Notably Japan has simplified regulatory requirements to improve the translation of cell therapies to the bedside. Within the USA several companies have been granted accelerated approval via the ‘fast-track’ pathway to commence MSC trials in the treatment of COVID-19-related ARDS.
How do you think MSC treatments for ARDS are perceived in the field?
The mechanism of action in using MSCs for ARDS means that developing this treatment offers an opportunity to intercept the inflammatory cascade that is responsible for tissue damage. This approach is both different and complementary to current treatment modalities that are primarily supportive. Therefore, I believe there is considerable hope in the field of critical care medicine for this treatment to significantly improve patient outcomes over what is already achievable. I also think that a perceived confidence in the potential of MSC applications in ARDS is derived from successful clinical developments in already approved MSC therapies for other immune modification scenarios such as graft versus host disease. Having said that, the broader medical community is not yet familiar with cellular therapies and so as with all emerging and expanding technologies, understanding and acceptance is still developing.
There have been clinical trials with MSCs for conditions such as ARDS previously. Why do you think there’s such variability in the results they produce?
First, I think the variability in results relates to the fact that preclinical success has not always been replicated in consistent positive clinical outcome. This may be due to biochemical markers commonly measured in preclinical trials not always being associated with subsequent clinical improvement. Second, the mode of application for in vitro and ex vivo analysis will differ considerably to clinical application and therefore may result in different outcomes. Third, the dosing of MSC therapy remains debatable with significant differences amongst clinical trials in regard to cell number and frequency of treatment. Fourth, MSCs are known to be a heterogenous cell population and the specific tissue source and cell line of allogeneic MSCs may impact upon both stability after multiple passages but also specific expression of immunomodulatory or reparative cytokines.
How do you see MSCs being utilized in the treatment of ARDS in the future?
Importantly, systematic review of clinical trials assessing the use of MSC therapy has indicated excellent safety. The current international environment and devastating impact of COVID-19 infection has seen MSC therapy emerge as a promising treatment. Whilst we need to remain focused on appropriate, safe and well-structured therapy development, this may represent a watershed moment where the broader medical community shifts to embrace the promise and hopeful clinical success of cellular therapies.
The opinions expressed in this interview are those of the interviewee and do not necessarily reflect the views of RegMedNet or Future Science Group.