Humans are the ultimate animal models of human diseases, but as humans there are limitations in their use, particularly to investigate inherited diseases and to develop therapies. We need to explore how we can optimise the use of both human and non-human models in understanding inherited diseases and developing therapies, but also to be innovative in developing novel ways of studying humans.

As clinicians, our clinical practice revolves around our interactions with patients. We obtain a history, perform an examination, investigate appropriately, make diagnoses, and instigate and monitor a treatment plan. It may therefore seem obvious that humans should be the ultimate animal models to use to further our understanding of the causes and treatments of human diseases. The COVID-19 pandemic brought this sharply into focus. When confronted with a major new pandemic in humans, urgent clinical studies, epidemiological studies and therapeutic trials in humans were necessary alongside the crucial laboratory studies to bring the pandemic under control. Luckily pandemics on this scale are extremely rare compared with many of the diseases we deal with, including most inherited neurological diseases which are often chronic and disabling. The limitations in using humans as disease models, especially in therapy development, has necessitated the development of multiple other in vitro (immortalised cell lines and human induced pluripotential stem (IPS) cells) and in vivo ((including invertebrate (Caenorhabditis elegans (roundworm), drosophila) and vertebrate (zebra fish, rodent and non-human primate) disease models. While these have been and remain invaluable, there are limitations to all these preclinical models as shown by the number of therapies developed and successfully tested in animal models that then fail in human clinical trials.1

The last 25 years has seen an explosion in the understanding of the genetic basis of diseases and especially neurological diseases. The increasing identification of new genes has been accelerated by the development of next generation sequencing techniques, especially whole exome (WES) and whole genome sequencing (WGS). In the area of inherited neuropathies there are now over 100 causative genes.2 In one of these diseases, TTR amyloidosis, gene silencing therapy is now in clinical use and in many others clinical trials of a range of therapies are ongoing. …