Nanoscale, secreted sacs called exosomes bud off from cellular membranes to fulfill diverse functions such as remodeling the tissue matrix and transmitting signals. Their important roles in many aspects of human health and disease, make them ideal therapeutic agents or delivery systems in treating multiple diseases.
In a new preclinical study published by Capricor Therapeutics, a biotechnology company focused on developing exosome-based therapeutics, and their collaborators at the United States Army Institute of Surgical Research (USAISR), scientists explore the therapeutic potential of exosomes isolated from a population of regenerative progenitor cells that give rise to cells in the heart.
The authors use exosomes called cardiosphere-derived exosomes (CDC-EVs) to treat a rat model of acute traumatic coagulopathy (ATC)—where blood in circulation clots due to trauma. The findings are reported in the article titled, “Extracellular vesicles derived from cardiosphere-derived cells as a potential antishock therapeutic” published in The Journal of Trauma and Acute Care Surgery.
Linda Marbán, PhD, Capricor’s CEO and co-author on the paper says, “This has been a key collaboration between the USAISR and Capricor and shows the importance of CDC-EVs as a potential anti-shock therapeutic. The military continues to look for therapeutics that can be delivered in the field to stabilize wounded warriors. While cell therapy held promise in that arena, a lyophilized product that does not require ultra-cold storage is preferable. We believe that our CDC-EVs could potentially be that product.”
The first order of business to allow the use of CDC-EVs in the treatment of ATC is to demonstrate that they themselves do not promote clotting of blood upon injection. To establish this, the authors use flow cytometry to evaluate the expression of factors on the surface of CDC-EVs that induce blood coagulation, viz., tissue factors and phosphatidylserine.
The authors test CDC-EV’s thrombogenicity—the tendency of a material in contact with blood to produce a thrombus or clot—using a calibrated thrombogram. They assess clotting parameters using a flow-based adhesion model simulating blood flow over a collagen-expressing surface. This assessment reveals CDC-EVs do not induce clotting and do not interfere with platelet function-one of the primary mediators of blood coagulation.
They then measure the therapeutic efficacy of CDC-EVs in a rat model of acute traumatic coagulopathy where trauma is induced through multiple injuries and hemorrhagic shock. Here, the authors show early administration of exosomes in the rat model of ATC markedly reduces the abnormally increased levels of lactate and creatinine in the rat and does not increase clotting. They also show CDC-EVs offset kidney damage and promote new blood vessel formation (angiogenesis)—both important factors in post-trauma recovery.
These findings show early administration of CDC-EVs have the potential to be used in treating shock and trauma and support the development of exosome-based products for use in combat casualty care. “While further work is required to elucidate the full extent of possible clinical implications for CDC-EVs in treating trauma, these results certainly are a very important first step in that evaluation. We are delighted to work with the USAISR and look forward to extending this collaboration,” says Marbán.
The authors note, “Research using CDC-EVs in trauma care needs to be considered and expanded beyond their reported cardioprotective benefits.”
A growing body of evidence from other preclinical studies supports the use of exosomes isolated from cardiosphere-derived cells in treating diseases by harnessing their anti-inflammatory, anti-fibrotic, pro-angiogenic, and anti-apoptotic effects. CDCs have been studied in over 100 peer-reviewed research article and have been administered to over 200 human subjects in several clinical trials.
Capricor’s lead candidate, CAP-1002, is a cardiac cell therapy that is currently in clinical development as a treatment option for Duchenne muscular dystrophy (DMD) and COVID-19. Marbán says, “We believe that the mechanism of action of our lead product CAP-1002 are these exosomes, and we have seen positive clinical data with these cells in multiple studies. Of note, we are currently enrolling our Phase II, INSPIRE study with CAP-1002 treating, severe COVID-19 patients. Since one of the pathological sequela to trauma is a hyperimmune response similar to that which we see in COVID-19 patients, we look forward to sharing the data from INSPIRE when it becomes available.”
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