Dr Lorenza Lazzari, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico; Dr Mario Barilani, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico
Disorders characterized by ischemia/reperfusion (I/R), such as myocardial infarction, stroke, and peripheral vascular disease, continue to be among the most frequent causes of debilitating disease and death. The brain is the most sensitive organ to I/R and the acute ischemic stroke (AIS) is the second leading cause of death and dementia, and the first cause of disability in adult humans, with a global incidence of 76-119 cases per 100,000 inhabitants per year. Currently, no broad and effective therapeutic approaches are available most of all due to the very short timeframe (3-6 hours) from stroke symptom onset in which a patient is eligible to receive the tissue plasminogen activator, the only thrombolytic agent able to reduce the secondary effects of ischemia. For the same very limited therapeutic window, AIS cannot benefit from the promising and effective human stem cells, nowadays widely tested in regenerative medicine.
The challenge of the inventors has been to discover and develop a new way to tackle with the inflammation which represents a primary player in the secondary damage effects on the ischemic tissue. The solution herein proposed is the novel use of stem cell-based cell-free product able to convey reparative and protective information in the form of bioactive molecules.
In the regenerative medicine field, the extracellular vesicles (EV) are more and more recognized as the central actors of the stem cell functional properties. EV are cytoplasm-containing cellular bodies carrying miRNA and other biological molecules. The inventors selected cord blood (CB) as the most convenient primitive stem cell source to isolate primary human mesenchymal stem cells (MSC), renowned for their beneficial effects in pathological contexts of acute damage. To establish an immortalized and reproducible stem cell line, an MSC batch was reprogrammed thanks to a zero-fingerprint method (repCBMSC). A specific set of miRNA able to modulate inflammation was identified. This set of miRNA was successfully challenged in a model of brain ischemia, where necrosis was significantly reduced. Intriguingly, astrocytes were the neural population more efficiently protected by EV. This protective/reparative effect correlated with significant tissue level reduction of apoptotic/inflammatory TNFα (4-fold) and INFγ (3-fold).
These repCBMSC-Extracellular Vescicles could be industrially produced in a ready-to-use formulation, so that clinicians could use them as soon as a therapeutic need arises, also in the case of an emergency treatment. Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico offers a patent license opportunity as well as a research collaboration with licensing option.
The plan is to work towards an in vivo proof-of-concept.
Priority application has been filed on December 06, 2017.
Ragni E, Banfi F, Barilani M, Cherubini A, Parazzi V, Larghi P, Dolo V, Bollati V, Lazzari L. Extracellular vesicle-shuttled mRNA in mesenchymal stem cell communication. Stem Cells 2017, doi: 10.1002/stem.2557