Ludwig Boltzmann Institute for Nanovesicular Precision Medicine

As we age, there is an increasing risk for chronic diseases and functional deficiencies. In particular, the occurrence of cancer, neurodegenerative diseases and defects of the musculoskeletal system rises with extended life expectancy. The WHO has recognized this serious public health issue as it limits the quality of life of the individual and poses a significant financial burden on healthcare systems. Managing and treating many of these late adult-onset disorders is currently limited by the lack of safe and effective therapeutic options that are precisely targeted to the patient’s situation. While traditional small molecule drug discovery reaches its limits, future breakthroughs are expected from approaches that turn natural systems into therapeutic modalities, such as immune checkpoint inhibitors, therapeutic antibodies, nucleic acids, gene editing or cell therapy. However, many of these new modalities show poor bioavailability due to low permeability and/or rapid clearance, thereby severely limiting their clinical application.

Extracellular vesicles (EVs) are the body’s own solution to this very problem. Nanosized secreted vesicles continuously circulate the body to transfer molecular cargo between cells, tissues and organisms, affecting fate and function of their recipient cells both nearby and at a distance. Utilizing this evolutionarily established nanovesicular trafficking system may enable the effective delivery of non-drug like molecules across biological barriers with the potential for cell and tissue targeting, while being highly biocompatible. In addition, EVs mediate cellular cues in modulating their environment, which makes them attractive surrogates for cell therapy. Despite the disruptive biomedical potential, however, a number of essential scientific, technological and practical challenges remain to be resolved.

The LBI for Nanovesicular Precision Medicines has the mission to translate knowledge on the biology of vesicle-mediated cell communication into the development of EV-based precision medicines to make an impact on clinical practice, public health, the economy and ultimately the environment. Our consortium uniquely combines highly complementary, trans-disciplinary EV expertise, ranging from fundamental EV biology, nanotechnology, bioanalytics, cell and vesicle engineering, pharmaceutical drug development, and GMP compliant pharmaceutical manufacturing to clinical application and regulatory affairs. Together we have a successful track record in establishing Salzburg as an internationally competitive research hub for Extracellular Vesicle Theralytic Technologies (‘EV-TT’, 2019-2022, funded by the State of Salzburg and the European Union). This new LBI will build on the scientific knowhow and cross-sectorial networks generated within EV-TT to develop nanovesicular precision medicines with a focus on three areas:

First, we will develop a next generation drug delivery platform that will enable safe, effective and targeted delivery of new therapeutic modalities such as RNA drugs, CRISPR-Cas gene editing therapeutics and heterobifunctional ligands (‘molecular glue’). By investigating the converging biology of physiological, pathological and synthetic nanovesicles, we aim to merge the safety of EVs with the efficacy of viruses and the practical feasibility of liposomes. The innate tropism of EVs from different sources will be further tailored by chemical surface engineering to specifically target the affected tissues. We will develop novel strategies for cargo loading into EVs and processes for industrially feasible and environmentally sustainable manufacturing at scale. Our major ambition is the development of therapeutic candidates for cancer and neurodegenerative diseases, with a focus on oral administration using food derived EVs. By extracting EVs from whey and other waste streams of industrial food processing we will directly contribute to sustainable use of resources, circular economy and meeting European green-deal objectives.
Second, we will take advantage of the inherent anti-inflammatory and pro-regenerative activities of EVs from human primary stem cells and breast milk to develop novel treatment modalities for musculoskeletal and neurodegenerative indications. Emphasis will be given to the immune modulatory and anti-fibrotic activities of EVs to reduce or delay scar formation to benefit the body´s own repair mechanism. Focus areas include rheumatoid arthritis, cochlear implant-induced foreign body reaction, tendon-bone entheses and chronic postoperative neuropathic pain. We will develop novel apheresis-based modalities for systemic immune cell modulation and investigate suitable clinical scaffold systems that support the topical application of EVs for wound healing augmentation. Capitalizing on the unique GMP manufacturing environment and expertise within the consortium, specific attention is given to the clinical translation potential and the regulatory compliance of the developed nanovesicular therapeutics.
Third, both biomedical research programs will be supported by side-by-side nanovesicular technology development. This will include (i) a comprehensive catalogue of quantitative bioanalytical methods for physicochemical and molecular EV characterisation and quality control down to the single vesicle – single molecule level, (ii) advanced imaging technologies (fluorescence, MRI, PET) to quantitatively track in vivo EV biodistribution at the whole animal, organ, tissue, cellular and subcellular level and (iii) label free approaches to monitor spatio-temporal EV cargo distribution using spatial genomics and single cell RNA-sequencing. Building on these technological capabilities, we will systematically catalogue the pharmaceutical potential of nanovesicles from diverse sources across all kingdoms of life, and co-develop potential biomarkers for clinical monitoring of therapeutic responses to the nanovesicular drugs.

With this comprehensive program we anticipate the following major deliverables of direct impact to the society: (1) development of nanovesicular precision medicines for safe and effective treatment of chronic and adult-onset diseases (cancer, neurodegeneration, tissue repair) as a public health issue of the aging population, (2) sustainable use of resources by valorising EV-containing side streams of industrial food processing for pharmaceutical use thereby (3) directly contributing to the CO2 reduction goals of the European green deal.