MHH

Heart failure (HF) is a most common cause of mortality with currently >60 million of affected patients. Numbers will increase due to socioeconomic factors and as a result of the current COVID-19 pandemic. A major underlying cause of HF are cardiac remodelling processes at the molecular, cellular and tissue level. We will here focus on noncoding circular RNAs (circRNA) involved in two distinct forms of cardiac injury, chemotherapy-induced cardiotoxicity and SARS-CoV-2-infection, where currently no specific treatment strategies are available to reverse disease pathology. First proof-of-concept studies targeting the cardiac remodelling process by noncoding RNA modulation have been pioneered by us and were recently tested in a world-wide first clinical phase 1b study in HF patients. Within the family of non-coding RNAs, circRNAs are stable and species-conserved and thus ideal drug targets. We discovered multiple molecular circRNA signatures during remodelling of cardiac cells and tissues from mice and patients. We now aim to lift our research to its next inflection point with the following steps and interconnected objectives: a) discover key functional circular RNAs involved in remodelling processes by functional CRISPR-Cas library screening; b) validate circRNAs by manipulating human living beating myocardial tissue, c) explore their mode of action; and d) perform targeted cardiac delivery approaches of selected candidates in both chemotherapy-induced cardiotoxicity and SARS-CoV-2-induced cardiac disease models. A combination of bioinformatic, molecular and physiology-based methods, unique established noncoding RNA drug discovery pipelines, availability of modern S3-safety labs, large clinical biobanks and (fresh) human cardiac tissue for slicing preparations form the basis for a successful strategy. REVERSE aims to discover fundamentally new therapeutic entry points for two forms of cardiac injuries, where currently no disease-specific treatments are available.

Acute myeloid leukemia (AML) remains a devastating disease, while progress in genetic characterization and nanomedical approaches promise a new era of individualized treatments. To prioritize genetic aberrations in AML for therapeutic targeting and to develop a pipeline for personalized nanomedicines I will i) establish a biobank of transplantable primary human AML xenotransplants, ii) fully characterize the genetic landscape of these leukemias, iii) establish the functional hierarchy of driver and passenger mutations in these human leukemia models, iv) develop highly efficient nanoparticle-siRNA formulations that allow in vivo delivery of siRNA to primary AML blasts, and v) design double specific siRNA-based nanomedicines for improved efficacy and tolerability. The expertise of my research team and my institutional settings and collaborations provide a unique platform to achieve these objectives. My access to freshly isolated leukemia blasts allows efficient establishment of a biobank for AML xenotransplant models. In fact, we can serially transplant and expand primary AML cells in immunodeficient mice. The biobank will be an invaluable resource for pharmaceutical product development. I have extensive experience in the genetic characterization and functional evaluation of leukemic cells, which I will apply to the newly generated human AML models. I will use inducible lentiviral approaches to genetically modify human leukemia cells and observe the functional effects in vivo, to identify the relevant targets for leukemogenicity of each primary AML model. Most importantly, I can formulate nanoparticle-siRNA systems that show unprecedented complete uptake into human leukemia cells in vivo and open the door for specific inhibition of any gene. These established tools provide me with the unique ability to develop a pipeline for individualized nanomedicines that will improve AML treatment and will also have broad applications beyond leukemia treatment.

The most prevalent genetic sensory defect, sensorineural hearing loss (SNHL), affects >430 million people and results in substantial financial and social consequences. Current treatment options are limited, achieving only temporary or partial relief and are restricted to a sub-group of patients. Therefore, novel treatment options are of high clinical need. Genetic mutations play a role in the majority of SNHL cases, which makes SNHL an ideal setting for innovative clinical gene therapy approaches. Usher syndrome is an especially severe form of SNHL, with loss of vision and balance accompanying the profound deafness. The size of the underlying genes, mutations of which are causative for Usher syndrome, exceeds the cargo capacity of gene therapy vectors currently employed to treat inner ear disorders. In my ERC-funded consolidator project iHEAR, we have provided the first ground-breaking evidence of efficient gene transfer into inner ear cell types using beyond state-of-the-art lentiviral vectors (LV). As these LV have the capacity to deliver large genetic payloads, we acquired initial data demonstrating functional improvement in a knock-out mouse hearing loss model following LV application. The MY(O)SENSES PoC proposal aims to advance these valuable research results towards clinical application by completing pre-clinical development, securing IP rights and commercializing a formulated medicinal product to launch a first-in-human clinical LV gene therapy trial to treat Usher syndrome patients. This ground-breaking concept can be extended to treat late-onset hearing loss in patients with heterozygous mutations and can be transferred to similar diseases with a genetic or acquired cause. The MY(O)SENSES product will be the first and only treatment that addresses the debilitating vertigo in combination with treating hearing loss in Usher syndrome patients, having the potential to drastically improve patients' lives and benefit society.