Degenerative diseases of old age, including cardiovascular diseases, stroke, type II diabetes, and chronic respiratory conditions, have emerged as the major causes of death in EU countries. Of special concern are neurodegenerative conditions including Alzheimer's (AD), Parkinson's disease and other dementias, which have been described as the greatest unmet need facing modern medicine. Developing new therapies to slow, halt, or reverse these pathologies is regarded as a key element in addressing this global health priority. Unfortunately, no prognostic biomarkers of degeneration are available with which to predict whether a candidate disease-modifying therapy is likely to improve clinical outlook. As a consequence, there is an unmet need for prognostic biomarkers of degeneration that can improve the ability of pre-clinical research to correctly predict future clinical benefit.
Our solution to this problem is relevant to a broad range of degenerative conditions and the aging process itself. It exploits the fact that, whilst degenerative diseases are complex and multifactorial, they share a fundamental and universal feature in that their pathogenesis and progression is associated with accumulation of cell damage mediated by oxidative stress (OS), inflammation, DNA damage and other conserved mechanisms. Under the ERC Advanced Investigator Award REDOX, we developed a portfolio of advance reporter mouse models in which these types of stress can be monitored non-invasively, in real time and at single-cell resolution across all organs, tissues, and cell types. In this Proof of Concept grant, NEW-AGE, we have interrogated whether these reporter models could be used as surrogate markers, and therefore as pre-clinical models, to improve the drug discovery process for diseases of old age.
In this programme, we have studied three neurological degenerative diseases - Alzheimer's, Parkinson's and Progeria. The reporter models generated in the ERC REDOX Advanced Investigator programme were crossed with representative models of Alzheimer's disease (hBACE1-KI), Progeria syndrome (LmnaG609G) and Parkinson's disease. We interrogated the activation of the reporters in a comprehensive panel of tissues by immunohistochemistry and in vivo bioluminescence in these models. Of particular significance, we observed that the stress reporters are elevated at prodromal stages in the Alzheimer's disease-DNA damage reporter model and both the Progeria-OS/inflammation and Progeria-DNA damage models. The increased reporter expression was time-dependent and in specific disease-relevant tissues. The project has therefore produced novel, proof-of-principle data indicating that these reporter systems can be used as early biomarkers of neurodegenerative disease and ageing. This exciting development will allow studies to assess whether reporter activity can be reduced by disease-modifying therapies. Therefore, these new disease-reporter models have the capacity to accelerate the development of new therapeutic interventions and reduce the costs of pre-clinical research. The work has also demonstrated that the attenuation of stress reporters can potentially be used as in vivo biomarkers of drug efficacy in clinical trials.
