OPEN-SESAME will assess the technical and commercial feasibility of a modular microbubble platform technology to enhance the delivery of drugs across biological barriers. The project aims to: (i) establish a robust and scalable synthesis protocol for producing shell- and shape-optimized polymeric microbubbles; (ii) evaluate the preclinical performance of our ultrasound-responsive microbubble enhancers in brain and tumor mouse models; (iii) strengthen our intellectual property (IP) position through freedom-to-operate investigation and generation of new IP on microbubble functionalization; (iv) consult key opinion leaders and perform market analysis of the drug therapy enhancer landscape; and (v) consolidate results in an investor-ready business plan to guide the commercialization of our microbubble platform. We anticipate that by exploiting the technological and socio-economic potential identified in the OPEN-SESAME project, we will create completely new opportunities for the use of microbubbles plus ultrasound to enhance drug delivery and improve therapy outcomes in patients suffering from high-medical-need diseases.

Chronic kidney disease (CKD) is a major global health problem, affecting 10% of the world population and projected to be the fifth major cause of death in 2040. CKD patients are one of the most complex and multi-morbid populations in internal medicine while at the same time having the least translational randomized clinical trials and limited treatment options. One of the major reasons for this is the lack of reproducible approaches specifically reflecting intrarenal pathological processes and disease activity. The overall goal of AIM.imaging.CKD is to specifically address this unmet need by developing, validating and integrating image-based diagnostics for CKD. The integration of broad interdisciplinary expertise will enable to develop a multiscale approach from nano- to micro- to macromorphological and molecular diagnostics. Specifically, the project will develop augmented full-spectrum ultrastructural (“nano”) and histological (“micro”) renal biopsy diagnostics, focusing on reproducible, quantitative nephropathological analyses and prediction of clinically relevant outcome parameters. The project will also explore macro-morphological and molecular imaging in CKD, focusing on translatable non-invasive approaches. The central feature will be the development of advanced, scalable and modular image analyses models utilizing artificial intelligence (AI), particularly machine and deep learning. Using preclinical testing and clinical validation, the main emphasis will be on accelerated or, whenever possible, direct implementation into the clinical practice. The integration of the above-mentioned tools and technologies provides a comprehensive multiscale and multiplex approach for improved diagnostics of CKD patients and facilitate future randomized clinical trials. At each level, and even more so when integrated, the results are expected to augment and transform image-based diagnostics of kidney diseases, and thereby lead to improved patient management and outcome.

Immunotherapy holds great promise for curative cancer treatment. While immune checkpoint inhibitors can induce complete and long-term cures, the percentage of patients responding to immunotherapy remains to be low. Combining immunotherapy with chemotherapeutic drugs that induce immunogenic cell death (ICD) is among the most promising strategies to potentiate antitumor immune responses. Chemotherapeutics are clinically typically administered via intravenous infusion, once every couple of weeks, at high doses. Metronomic dosing is based on the application of chemotherapy drugs at high frequency and low doses, and it is gaining increasing interest to potentiate chemo-immunotherapy responses. However, high-frequency low-dose chemotherapy administration in the clinic via intravenous infusion is pragmatically undoable and economically not feasible. At-home administration via oral ingestion or subcutaneous self-injection is impossible, because of the side effect spectrum of chemotherapeutic drugs. In the PRIME project, we aim to establish PRodrug technology for Immunotherapy-priming via patient-friendly at-home MEtronomic dosing. Prodrugs have assisted in improving drug performance for over a century now, and they are widely employed in pharmaceutical industry and clinical practice, with approximately 10% of new drug approvals technically being prodrugs. We will set out to establish a synthetic and formulation strategy to produce a novel immunogenic prodrug platform, and upon subcutaneous metronomic dosing, we will evaluate the preclinical performance of our prodrugs as monotherapy and in combination with immunotherapy in breast and prostate cancer mouse models. We anticipate that exploiting the technological and socio-economic potential of PRIME will unlock new avenues towards at-home cancer treatment opportunities with enhanced therapeutic outcomes and improved patient quality-of-life.

Fibrosis is estimated to be involved in 45% of global mortality, and currently no specific therapies for fibrosis in most organs exist. One central and controversially discussed question in the field of organ fibrosis is: “is fibrosis truly reversible”? In Rewind-MF, I will address this biologically and clinically highly relevant question in a prime example: bone marrow fibrosis in a chronic blood cancer called Primary Myelofibrosis (PMF). In PMF, hematopoietic stem cells become mutated and activate fibrosis-driving cells. Fibrosis reversal in PMF is possible through allogeneic stem cell transplant (ASCT). However, the majority of patients are not eligible for this high-risk procedure. Alternative fibrosis-reversing strategies are not available, leaving this patient group without any treatment option. My specific aims in Rewind-MF are: (1) to gain spatio-temporal insights into fibrosis reversal and mutant clone elimination mechanisms to predict, which patients will benefit from ASCT, and to identify therapeutic targets; (2) to understand how blood cancer is maintained in the bone marrow and later the spleen stroma in order to find new ways to reverse fibrosis, and eradicate the cancer cells, and (3) to validate fibrosis reversal mechanisms and translate them into clinically relevant therapeutic strategies. What makes Rewind-MF unique is the holistic “bench-to-bedside” approach starting from a stem cell biological hypothesis [tested by innovative murine models and (stem) cell approaches], advanced by a broad interdisciplinary expertise with novel single cell, spatial genomic and computational technologies, to dissect mechanisms of fibrosis reversal and develop therapeutic approaches which go beyond pure target identification. The integration of all these technologies in clinically relevant specimens with follow-up data and large independent validation cohorts will truly revolutionize the prognostication and (personalized) treatment of patients with MF.

Chronic kidney disease (CKD) is a progressive disease in which kidney function is gradually lost. It can develop consequent of many (kidney) diseases and it affects more than 10% of the world population. Although in recent years sodium–glucose cotransporter 2 inhibitors and novel non-steroidal mineralocorticoid antagonists are showing significant effects on CKD, the majority of patients treated still progress towards end-stage renal disease (ESRD). With dialysis or kidney transplantation as the sole treatments available in case of ESRD, the disease represents an enormous burden on healthcare costs throughout Europe. Caused by organ injury, fibrosis leads to replacement of functional tissue and organ architecture by extracellular matrix, leading to tissue scar formation and impaired function of the affected organ. This makes fibrosis a key therapeutic target to improve organ function in e.g., CKD. Myofibroblasts are the key driver cells of fibrosis across organs and research in our lab has demonstrated that targeting myofibroblasts stabilises organ function. Additionally, we have identified GLI1/2 as a myofibroblast cell-cycle progression-specific target. We found that the number of Gli proteins, transcriptional effectors of the Hedgehog signalling pathway, are significantly increased in the kidney after injury. Furthermore, GLI1/2 are ideal targets as they are not expressed during homeostasis in adults. DISRUPT-KF will validate a set of novel Gli inhibitors as disease-modifying drug candidates for CKD. Preliminary evidence shows anti-fibrotic efficacy in human 2D culture platforms and in induced pluripotent stem cell-derived kidney organoids in vitro. During DISRUPT-KF we will further verify and optimise the anti-fibrotic drug candidates in relevant in vitro (kidney fibrosis organoids) and in vivo (mice) models to validate their potential. We will also develop and execute an IP strategy and a commercial feasibility analysis to enter the anti-fibrotic CKD market.