Digestive fistula therapy by extracellular vesicles delivered into a thermoresponsive hydrogel – FisTher

Fistulas are a major neglected health burden related to Crohn's disease or secondary to surgery, cancer therapy or trauma. Post-surgical digestive fistulas are challenging conditions associated with low remission rates and high refractoriness. There is an urgent need of novel therapeutic approaches for this disease. FisTher investigates an alternative to cell therapy approach, by proposing a minimally-invasive cell-free local therapy based on the regenerative effect of extracellular vesicles (EVs) from mesenchymal stem/stromal cells (MSCs). We consider that MSC EVs represent an eligible alternative for fistula therapy, as they recapitulate the regenerative effect of their mother cells while mitigating risks of uncontrolled replication, differentiation and vascular occlusion, offering “off-the-shelf”, storage and shelf-life gains. The main challenges for rendering EV-based regenerative medicine clinically feasible are large-scale high-yield standardized EV production and EV optimized administration. Concerning EV manufacturing, stringent requirements must be considered such as up-scaled and high-yield production fulfilling uniformity, consistency, purity and reproducibility criteria based on standardized and reliable quality control. The way EVs are administered also represents a main concern considering that systemic administration results in rapid EV clearance and localization in off-target organs.
Building on the PI previous work, our strong preliminary results, our intellectual property and complimentary collaborators, FisTher has the ambition to render viable the implementation of EV-based therapy by tackling EV production and administration technical barriers. FisTher proposes large-scale high-yield EV production based on our patented concept of turbulence-vesiculation complying with a standardized production in GMP bioreactors in line with regulatory issues. FisTher set-up relies on the generation of a controlled turbulent flow in which turbulence microvortices will elicit a shear stress on cells triggering EV release. This turbulence-based strategy is (i) time-saving enabling massive EV release in some hours, (ii) integrated as it is based on tuning the own GMP bioreactor stirring system, (iii) straightforward as no further processing is required to eliminate the trigger (turbulence disappearing when stirring is turned off) and (iv) scalable based on turbulence flow parameters. FisTher also proposes a thermo-actuated EV delivery in the fistula tract for eliciting an enhanced therapeutic effect in situ. FisTher strategy is expected to avoid systemic administration clearance and overcome difficulties related to local delivery, such as fistula secretions (washing-out the therapeutic agent) and fistula tract inaccessibility (sometimes irregular large defects of several centimeters). FisTher relies on dual biomaterial/EV component for fistula therapy. The thermoresponsive hydrogel biomaterial component is expected to cope with fistula local delivery difficulties promoting an occlusive effect, retaining EVs in the fistula tract and preventing EV wash-out by fistula secretions, while enabling the filling of the entire fistula tract despite its size and irregular morphology. Biomaterial choice was based on material physical and therapeutic properties and considered a clinical translation perspective. Building on strong preliminary results, we intend to investigate the combination of turbulence EVs with a poloxamer 407 hydrogel. FisTher proposes the off-label use of this hydrogel, which is a vessel occlusive medical device authorized in Europe, as an innovative fistula occlusive EV vehicle.
FisTher fully considers key regulatory and manufacturing issues in the project choices to set the basis for implementing the first future clinical trial on MSC EVs for the therapy of post-surgical digestive fistulas.