For many years, traditional drug development relied heavily on rodent pharmacology. However, the translational value of rodent models is often questionable, as demonstrated by clinical failures of drug candidates despite convincing efficacy in rodents. The total number of rodents used in animal studies is declining. According to the German Federal Ministry for Food and Agriculture 1.64 million rodents were used for scientific purposes in 2019, down from nearly 2.4 million in 2009. This represents a reduction of more than 30 %. This trend reflects an urgent need for re-evaluation of translational strategies to increase clinical efficacy.
Alzheimer’s Disease
Two hundred and five rodent models of Alzheimer’s Disease (AD) are currently (Mar 2021) listed on alzforum.org. Hallmarks of AD pathology are accumulation of Aβ plaques and neurofibrillary tangle formation by hyperphosphorylation of tau, the major microtubule-associated protein. Numerous genetic models in rodents have been developed along these two avenues and treatment with drug candidates have been efficacious in important readouts such as spatial learning and memory. However, the well-known genes associated with familial AD (APP, PS1, PS2) used in many constellations of mouse genetics seem not to tell the full story, especially not for the most common form of late-onset AD. Pistollato et al. 2020 and many others have discussed potential reasons for clinical failures and strategies for improvement. Systems biology has started to paint a broader picture of AD by allowing the potential pathways involved in pathology to be described holistically and better represent the complexity of the human disease. Rayaprolu et al. 2021 report application of network-based proteomics for identification of novel avenues in AD. While amyloid and tau-based genetics of AD might only partially describe the underlying pathology and more complex interactions need to be considered, this complexity might also be reflected by animal models that more closely resemble the human situation than genetically modified mouse strains. Vikartovska et al. 2021 describe aging dogs as potential model for AD pathology. Like the human population, dogs are increasing in age in recent decades due in part to increased owner care, improved diet, and improvements in veterinarian medicine. The concept of aging companion animals is not new to the discussion of AD, but few studies have been performed in these animals compared to the outsized number of studies in rodents. Finally, iPSC-based approaches to AD and other CNS indications are becoming increasingly available. Qian and TCW 2021 recently reviewed the state-of-the-art, which for now focuses on the well-known amyloid and tau-based genetics reflecting the development of mouse genetics. Nonetheless, the technology is advancing, giving us tools for drug discovery to evaluate candidates in 2D or 3D organoid preparations.
Conclusion
Rodents will remain an important factor in advancing our knowledge of the CNS. However, the multitude of clinical failures in CNS indications such as AD ask for a more elaborated translational approach. Assessment of the disease complexity at a higher level in combination with alternative, spontaneously evolving disease models in companion animals and translating the resulting findings into “druggable” in vitro approaches based on human cellular assays should help improve the translational value of preclinical studies.
© Thomas Christoph
