Exosomes-EV-based Therapeutics Summit Agenda

Networking Lunch

Exosome-based Delivery of Therapeutic Proteins: Principles and Applications
Chulhee Choi, Professor and Chair, BioMedical Imaging Center, Korea Advanced Institute of Science and Technology (KAIST), President, ILIAS Biologics Incorporated, Korea South

Our group has recently developed an opto-genetically engineered exosome system, named ‘exosomes for protein loading via optically reversible protein–protein interaction” (EXPLOR) that can deliver soluble proteins into the cytosol of target cells via controlled, reversible protein–protein interactions (PPI). By integrating a reversible PPI module controlled by specific wavelength of light with the endogenous process of exosome biogenesis, cargo proteins of our interest can be loaded into the exosomes. Engineered exosomes were shown to significantly increase intracellular levels of cargo proteins and their function in the recipient cells in both a time- and dose-dependent manner. In this presentation, I will introduce the basic principles of EXPLOR technology and follow-up studies for therapeutic applications focusing on novel anti-inflammatory exosomes in various disease models.

Exosome, The Next Small Thing: A Winning Strategy to Lead its Manufacturing and Characterization
Behzad Mahdavi, Vice President of Strategic Innovation & Alliances, Lonza

• Importance of Exosomes in Precision Medicine and Targeted Delivery
• How expertise and assets in cell manufacturing are essential for Exosome manufacturing  
• Leverage the exosome-based liquid biopsy, characterization and profiling in therapeutic development manufacturing
• Cell Therapy Manufacturing + Exosomes Based Liquid Biopsy = A winning combination to lead Exosomes Manufacturing

An Exosome-based Drug Delivery Platform Derived From an Immortalized Human Neural Stem Cell (hNSC) Line
Randolph Corteling, Head of Research, ReNeuron Ltd., United Kingdom

To ensure the scale required for clinical research and commercialisation producer cell immortalisation and clonal isolation is a practical strategy to produce consistent, functionally bioactive exosomes for use as therapeutic agents. Immortalisation ensures production stability and reduces the need for equivalence testing.

CTX0E03 is a conditionally immortalised human neural stem cell line that has been manufactured to clinical-grade (GMP) standards, using a 3-tier banking strategy and is currently in Phase IIb clinical evaluation for disability after stroke. Using the conditioned media produced during GMP manufacture, we have shown that CTX0E03 is an abundant producer of exosomes that can be readily isolated and purified at scale. The CTX cell line can also be rapidly and efficiently modified to direct the expression of a variety of cargoes within the secreted EV population, whilst maintaining the key immortalised stem cell characteristics of the parental cell line.  The natural tissue tropism of CTX-derived exosomes can then be exploited to deliver loaded cargoes to target cells.

Mesenchymal Stem Cell-derived Extracellular Vesicles: A Potential New Tool in Regenerative Medicine
Bernd Giebel, Group Leader, Institute for Transfusion Medicine, University Hospital Duisburg-Essen, Germany

Human mesenchymal stem/stromal cells (MSCs) represent a promising tool in regenerative medicine. Up to now, more than 1000 NIH-registered clinical trials investigated their immunomodulatory and pro-regenerative therapeutic potential in various diseases, including graft-versus-host disease (GvHD) and ischemic stroke. Despite controversial reports regarding the efficacy of MSC-treatments, MSCs seem to exert their beneficial effects rather in a paracrine manner than by cell replacement. In this context, extracellular vesicles (EVs), such as exosomes and microvesicles, are discussed to execute the MSCs’ therapeutic effects. Indeed, we observed beneficial therapeutic impacts of MSC-EVs in a patient, who suffered from steroid-refractory acute GvHD. Furthermore, beneficial effects were observed in animal models for several different diseases.

According to controversial reports in the MSC field, especially since a phase III clinical trial failed to show clinical efficacy in MSC treated GvHD patients, we have started to compare immunomodulatory effects of independent MSC-EV preparations. Indeed, in our in vitro assays independent MSC-EV fractions reveal different immunomodulatory capabilities. To unravel the basis for these differences we are currently using several methods to dissect the heterogeneity between and within given MSC-EV samples.

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 Unit, Paracelsus Medical University Salzburg, Austria

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)

Round-Table Discussion on the Opportunities and Industry Trends in the Exosome/EV-Delivery and Therapeutics Space with Coffee

Close of Summit