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Regenerative medicines could have life-saving potential by dampening inflammation
The COVID-19 pandemic is one of modern medicine’s greatest challenges. There have been 20 million (and counting) confirmed cases worldwide and, if predictions are right, the worst is yet to come in the absence of a preventative or therapeutic drug. There is, however, cause for optimism with a long list of vaccines and antibody-based therapies currently in development. Besides these drugs, scientists are also using regenerative medicine paradigms as a source of inspiration for developing life-saving COVID treatments.
Inflammation: the common thread
Though seemingly unrelated, experimental treatments for neurological conditions have provided researchers with a breadcrumb trail towards potential COVID-19 therapies. Cell-based treatments, for example, have shown promise in improving outcomes after a stroke, a condition where blood flow to the brain is interrupted.
Oakland University’s Benjamin Buller is among the scientists demonstrating how mesenchymal stem cells, or MSCs, can help stroke patients. In the wake of the pandemic, Buller and his team have shifted gears, exploring how similar stem cell therapies could benefit COVID-19 patients instead. “When the COVID catastrophe started happening, what piqued my interest were the early reports of thrombosis and D-dimer elevation in patients,” said Buller at a recent webinar on regenerative medicine approaches to treat the coronavirus infection.
The common thread linking strokes and COVID-19 is inflammation. In both cases, pro-inflammatory chemicals flood tissues, immune cells begin to work in overdrive, and blood clotting pathways are set off. Infection by SARS-CoV-2 triggers a massive, systemic inflammatory response, which can culminate in the acute respiratory distress syndrome or ARDS. Here, fluid accumulates in the lungs’ alveoli — the tiny, elastic pockets within the lungs that take up oxygen. Once this critical stage of the disease is reached, around 40 per cent of patients succumb to their symptoms.
Many clinical biomarkers of brain trauma mirror those of ARDS, which means MSC-based treatments could benefit severe COVID cases too. “That suggests that there’s some sort of systemic, blood-based inflammation and the mechanisms at play may be similar to what happens after a brain injury,” Buller explains.
The discovery of exosomes
In early preclinical studies, Buller and other stroke researchers made stunning observations when MSCs were grafted onto damaged brain tissues: the stem cells differentiated into neurons, and the brain began to heal through tissue remodelling and the rewiring of its neural circuitry.
Follow-up studies identified the source of these powerful regenerative effects: microscopic “bubbles” secreted by stem cells that contain a rich cocktail of regenerative factors. These extracellular vesicles, or exosomes, are membrane-bound spheres that carry a cargo of various proteins, lipids and nucleic acids as a means of cell-cell communication. In animal models of stroke, purified exosomes showed spectacular results as a drug, mimicking the effects of stem cell grafts and significantly boosting cognitive and behavioral outcomes.
Breathing easy with MSCs
These studies set the stage for using exosomes to treat other inflammatory conditions. Though preliminary, results testing this hypothesis in COVID-19 are encouraging. Earlier this year, a small study showed that seven COVID patients injected intravenously with MSCs experienced a marked improvement in their recovery from ARDS.
Since then, the interest in stem cells for ARDS has skyrocketed. There are multiple clinical trials currently in progress investigating the safety and potency of these therapies. One such initiative is the CIRCA-19 (Cellular Immunotherapy for COVID-19-Related ARDS) trial, sponsored by the Ottawa Hospital Research Institute.
Duncan Stewart, CEO and Scientific Director of the Institute, thinks that stem cells may help patients bounce back from COVID via multiple modes of action, saying, “MSCs have the ability to dampen inflammation to prevent it from becoming as severe, while at the same time bolstering other aspects of the immune response to remove pathogens and allow the organ to heal.”
Exosomes are also in the spotlight for another possible clinical application — as a nano-platform for delivering COVID vaccines and drugs to the lungs. These particles can be loaded with nucleic acids encoding a vaccine or antibody against the SARS-CoV-2 virus, thus overcoming some of the limitations of synthetic drug carriers. In the future, COVID-busting exosomes could be easily administered to patients in the form of aerosol sprays, as opposed to injections or intravenous infusions.
All that glitters may not be gold
As with any up-and-coming drug, the clinical translation journey is rarely smooth sailing. MSCs and exosomes have proven their value under small scale, experimental conditions. But regulatory bodies demand that many other boxes are checked before they can make their clinical debut. For instance, drug developers need to be able to assure the purity and potency of each treatment dose — not so easy when MSCs from different donors are, by their nature, highly variable and heterogeneous. To address this, the stem cell research community is calling for more rigour around testing and validation before MSCs and exosomes are made into frontline COVID therapies.
Experts are confident that no one drug modality, be it a vaccine, drug or cell therapy, is likely to be a panacea. For now, it’s hard to predict which will have the biggest impact, especially considering that much is still unknown about this crowned viral killer. One thing, however, is clear: the thriving stem cell research and development ecosystem has served as a solid jumping-off point for the many scientists working tirelessly to design tomorrow’s COVID therapeutics.
For more blogs on the opportunities and challenges for regenerative medicine as the world recovers from COVID-19, visit Signal’s fifth annual blog carnival here.
Tara Fernandez
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