Disease-directed engineering for physiology-driven treatment interventions in neurological disorders.

Neurological disease is killing us. While there have long been attempts to develop therapies for both acute and chronic neurological diseases, no current treatments are curative. Additionally, therapeutic development for neurological disease takes 15 years and often costs several billion dollars. More than 96% of these therapies will fail in late stage clinical trials. Engineering novel treatment interventions for neurological disease can improve outcomes and quality of life for millions; however, therapeutics should be designed with the underlying physiology and pathology in mind. In this perspective, we aim to unpack the importance of, and need to understand, the physiology of neurological disease. We first dive into the normal physiological considerations that should guide experimental design, and then assess the pathophysiological factors of acute and chronic neurological disease that should direct treatment design. We provide an analysis of a nanobased therapeutic intervention that proved successful in translation due to incorporation of physiology at all stages of the research process. We also provide an opinion on the importance of keeping a high-level view to designing and administering treatment interventions. Finally, we close with an implementation strategy for applying a disease-directed engineering approach. Our assessment encourages embracing the complexity of neurological disease, as well as increasing efforts to provide system-level thinking in our development of therapeutics for neurological disease.