The Path to Progress Preclinical Studies of Age-Related Neurodegenerative Diseases: A Perspective on Rodent and hiPSC-Derived Models

Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the two most prevalent age-related neurodegenerative diseases, and currently no effective clinical treatments exist for either, despite decades of clinical trials. The failure to translate preclinical findings into effective treatments is indicative of a problem in the current evaluation pipeline for potential therapeutics. At present, there are no useful animal models for AD and PD research that reflect the entire biology of the diseases, specifically, the more common non-Mendelian forms. Whereas the field continues to seek suitable rodent models for investigating potential therapeutics for these diseases, rodent models have still been used primarily for preclinical studies. Here, we advocate for a paradigm shift toward the application of human-induced pluripotent stem cell (hiPSC)-derived systems for PD and AD modeling and the development of improved human-based models in a dish for drug discovery and preclinical assessment of therapeutic targets. [Display omitted] In light of the persistent failure to generate clinically effective disease-modifying therapeutics for neurodegenerative diseases, there is a pressing need to improve current research preclinical modeling systems for such diseases. MacDougall et al. advocate for a paradigm shift toward the application of state-of-the-art human-induced pluripotent stem cell (hiPSC)-derived systems for PD and AD modeling and the development of improved human-based models in a dish for drug discovery and preclinical assessment of therapeutic targets in an effort to improve the efficiency of the current drug-development pipeline.