Proposals submitted under this topic should tackle the above-mentioned issues and pave the way to secretome-based therapies that are safe, efficacious, and regulatory-approved for human use. The activities should cover secretomes or their parts that are derived from human cells and comprise all the following elements:

• The selection of a secretome-based therapy whose main mechanism of action has been elucidated in in-vitro and/or in-vivo models prior to the start of the proposed work. The selected secretome or its chosen bio-active components (extracellular vesicles, trophic factors, organelles, RNA, proteins, peptides, etc.), including those that are potentially harmful, should have been characterised and its/their therapeutic activity should already have been demonstrated in relevant pre-clinical models. All types of human cells may be used as underlying parent cells.
• All activities that are necessary to ensure regulatory and ethical approvals enabling the conduct of the clinical study. This may comprise the full characterisation, standardised analytical methods, further pre-clinical studies in relevant models (pertinent to the targeted disease or disorder) and appropriate quality assurance assays including computational approaches, organoids and organ-on chips/microfluidic systems.
• Establishment of a manufacturing protocol for the selected secretome or its components, including all the steps of the biogenesis: parent cells selection, their pre-conditioning and bio-processing (isolation, expansion, cultivation in bioreactors), processing of the conditioned media, the extraction of the secretome or its components (isolation, purification, storage, distribution) and its/their delivery to target site in the human body (mode of administration, final formulation).
• Definition of relevant quality criteria for and establishment of a fully GMP-conform production process that enables to carry out clinical trials of the proposed secretome-based therapy.
• Carrying out of all the above-mentioned activities in close interaction with and in compliance with all requirements of the relevant competent authorities, allowing to perform clinical trials.
• Conduct of an interventional randomised controlled clinical trial comprising phase 1 and phase 2 to generate scientific evidence demonstrating safety and efficacy of the proposed secretome-based therapy.
• Applicants are expected to deliver no later than at month 12 of the project the documentation needed for the GMP-conform production (e.g. SOP – Standard Operating Procedures) and no later than at month 24 the documentation needed for the conduct of the clinical trial (e.g. IMDP), enabling to get the regulatory approval for the clinical trial. The overall goal is to perform and finalise the phase 1 and phase 2 clinical trials during the lifetime of the project and further achieve authorization of the proposed secretome-based therapy.
• Optionally and if essential for the chosen secretome-based therapy, the work should also include an engineering step of the secretome to achieve the desired profile for increased safety and improved therapeutic effect. To this end, the secretome or its bioactive component(s) may be modified either pre- or post-biogenesis, by use of classical methods on the parent cells, except their genetic modification, or by physico-chemical modification of the bio-active secretome component. The effected modifications of the secretome should lead to the improvement of the functional properties/features and/or of the delivery to target site (organ, tissue, etc.) for the bioactive secretome component. All these modifications should not alter the main mechanism of action and retain the proposed secretome-based therapy within the boundaries of substances of human origin. The therapeutic effect of the secretome or its components should come from its/their endogenous capabilities and functionalities; exogenous loading with drugs (using the secretome or its components as drug carrier), be it pre- or post-biogenesis, is not in scope.

All types of diseases, dysfunctions or health impairments may be targeted, preference should be given to conditions that affect larger patient populations and/or represent a high burden on public health systems.

Sex differences should be taken into consideration, both with regard to the parent cells and for the targeted therapeutic application. Participation of small and medium-sized enterprises (SMEs) is strongly encouraged and if an exploitation strategy is developed, it should commit to a first deployment in the EU.