3R-conform models and GMP-grade GTMP production for highest quality in translationalresearch increasing welfare and safety for laboratory animals and patients

Non-human primates should be given granted basic rights; about this request decided a cantonal referendum (Basel) in 2022. In clinical practice, in 2024, a girl died from the adverse effects (AE) of a gene therapy trial, being not the first nor last but most recent tragedy in drug development (DD). How do these pieces of news fit together and what do they have to do with “good” research? The obligation for patient safety and the need for new therapies creates a conflict between human welfare and human rights with the rising request for regulations in animal welfare and animal rights. We are engaged in resolving the conflict by developing technologies that are both relevant for patient’s safety and efficacy and respect the rights of welfare for animals. Nowadays, DD involves 4 phases: Initial cell-based experiments, organoid or organ culture studies, animal testing, and clinical trials. While cell-based experiments yield rapid insights into a specific cell type, their lack of complexity and reliance on fetal bovine serum (FBS) present ethical and technical limitations. Organoids and organ cultures offer a higher level of complexity without the need for laboratory animals but face technical constraints and limited application. Animal testing allows for whole-organ analysis with all its interactions. It has, however, significant ethical concerns, limited translatability to humans, and regulatory requirements for testing in multiple species. Finally, a new drug is tested in patients including standardized, high-quality control (QC). Yet, this is difficult to implement particularly in Advanced Therapies, where risk-based QCs are established that cannot be standardized and are intended to minimize risks for severe unexpected AE but cannot exclude them. There are thus still major challenges to be met in DD. We develop therapies for the treatment of neuroretinal degeneration and conduct experiments in all the phases mentioned, through ethical practices aimed at patient safety. Three projects illustrate this commitment. First, we are establishing an FBS-free cell culture and are optimizing ex vivo retinal experiments to eliminate technical limitations, strengthen the significance and reduce reliance on animal experiments. Second, we have developed an improved age-related macular degeneration (AMD) model in 18-month-old mice. Third, we have established a transferable and standardized QC system for an AMD gene therapy. Together, these advancements align patient safety with ethical research principles and offer our patients innovative therapies that they can trust from the first cell experiment through clinical application.