Sight is the most treasured of our senses, followed by hearing and balance. Moderate to severe vision loss affects more than 216 million people worldwide, with an estimated 36 million people suffering from blindness. Monogenic diseases caused by mutations in genes such as MYO7A are responsible for vision loss in over two million people. As current treatment options for genetic vision loss are limited or non-existent, there is a high clinical need for innovative approaches, such as gene therapy. Usher syndrome type 1B (USH1B) is caused by MYO7A mutations and patients suffer from profound deafness accompanied with loss of balance and vision. In my ERC-funded consolidator grant iHEAR and Proof-of-Concept grant MY(O)SENSES, we showed the first ground-breaking data for efficient gene transfer with lentiviral vectors into inner ear cell types and correction of hearing and balance defects caused by mutated MYO7A. The EuroVision 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 USH1B patients. The EuroVision product will be the first and only single-vector treatment that addresses vision loss due to MYO7A mutations in USH1B patients, which has great potential to significantly improve quality of life for these patients as well as to benefit society through relief of costs associated with healthcare and lost productivity. Moreover, this ground-breaking therapy will lay the basis to address other monogenic eye diseases, in which large genes need to be transferred and for which there is an urgent medical need.

The HyperTargIPS-NK project aims to combine novel technologies from three research laboratories and a stem cell company to develop a revolutionary therapeutic modality for patients with devastating refractory malignancies. The treatment we propose is based on allogenic transplantation of induced pluripotent stem (iPS) cell-derived natural killer (NK) cells, genetically modified to a hyperactive state to ensure high potency NK cell targeting and destruction of tumor cells. CAR NK-based cancer treatment is an extremely promising new therapeutic avenue. However, the full potential of CAR NK therapies will only be achieved when an off-the-shelf product is rapidly accessible to patients in need. IPS with its unlimited expansion potential is the ideal cell source for NK-based products, however, improved efficiencies of NK cell production, suitably activated status, and resistance to immune suppression would need to be achieved. We have several breakthrough technologies to address these issues with 1) a novel iPS cell differentiation system based on our newly identified metabolic regulators that can be easily scaled to generate billions of functional NK cells, 2) identified and validated several novel and state-of-the-art CAR, non-CAR and TRUCK based regulators of NK activation to elicit the hyper activated NK cell state and prolonging NK survival, and 3) improved NK response to tumors via tumor microenvironment remodeling. We will target the NK cells towards three life-threatening cancers for which novel treatment options are urgently needed as they are considered among the most lethal cancers; i.e. Pancreatic cancer, Glioblastoma, and Acute Myeloid leukemia (AML). Our iPS culture system, NK activation systems, and gene editing systems, have already been designed towards GMP compatibility. Taken together, these advances ensure that once this study is successful, our Hyper-Targ-IPS-NK cells are poised for rapid translation towards the clinic with our industrial partner.