Abstract

First-In-Human Application of Umbilical Cord MSC-Derived EVs for the Prevention of Cochlear Implant Surgery-Related Injury

Mario Gimona, Head of Manufacturing-GMP, Paracelsus Medical University Salzburg

Cochlear implantation (CI) can restore hearing perception by bypassing the auditory hair cells (HC) and directly stimulating the spiral ganglion neurons (SGN). Insertion of an electrode array into the cochlea is associated with robust early and chronic inflammatory responses that promote intra-cochlear fibrosis and loss of HC and SGN. Conservation of residual hearing and prevention of fibrous tissue deposition around the electrode are thus major challenges in CI surgery. We have manufactured GMP-compliant umbilical cord (UC)-MSC- derived extracellular vesicles (EVs) and subjected such preparations to a series of in vivo and in vitro assays. Animal studies included both systemic and local injection for the improvement of seemingly unrelated indications such as critical size bone defects, partial tendon rupture and spinal cord injury in a rat contusion-model. In all cases EV application resulted in a significant modulation of immune reaction, overall reduced inflammation and scar reduction as evidenced by a reduction in ECM deposition. In an in vitro spiral ganglion neuron protection assay UC-MSC-EVs outperformed the current best-in-class soluble neuroprotective factor, BDNF. In vivo application of EVs in mice challenged by noise trauma resulted in significant protection of hearing when compared to untreated controls. Reduction of impedance as a measure for current resistance and fibrotic tissue formation around the electrode array were observed in a model of implantation trauma in guinea pigs implanted with an electrode array. After careful consideration of the medical history of a patient requiring CI surgery an experimental healing attempt was performed and the patient received a single intra-cochlear injection of 5 x 109 EVs (total) prior to electrode insertion. The application was tolerated well, no adverse reactions were recorded and robust auditory sensation was detected 6 weeks post surgery. Based on these initial safety data on the local application of EVs in the inner ear, a phase 1/2a clinical trial is currently in preparation to further evaluate the neuroprotective, immunomodulatory and anti-fibrotic potential of UC-MSC-EVs.

Funding:  Project “ Exothera” IT-AT 1036 (EU), Project “ExtraNeu” (Land Salzburg)